(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property Organization
Internationa] Bureau
(43) International Publication Date
21 November 2002 (21.11.2002)
(10) International Publication Number
PCT WO 02/092576 Al
(51) International Patent Classification 7 : C07D 239/34,
A61K 31/505, C07D 251/42, 239/47, 417/12, 401/12,
231/40, A61P 29/00
(21) International Application Number: PCT/US02/ 14733
(22) International Filing Date: 8 May 2002 (08.05.2002)
(25) Filing Language:
(26) Publication Language:
(30) Priority Data:
60/291,425
English
English
16 May 2001 (16.05.2001) US
(71) Applicant: BOEHRINGER INGELHEIM PHAR-
MACEUTICALS, INC. [US/US]; Raymond, Robert, P.,
Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridge-
bury Road, P.o.box 368, Ridgefield, CT 06877-0368 (US).
(72) Inventors: CIRILLO, Pier, F.; 180 Washington Road,
Woodbury, CT 06798 (US). GOLDBERG, Daniel, R;
31 Highland Avenue, Redding, CT 06896 (US). HAM-
MACH, Abdelhakim; 8 Rolf's Drive, Danbury, CT 06810
(US). MOSS, Neil; 199 Barlow Mountain Road, Ridge-
field, CT 06877 (US). REGAN, John, Robinson; 287
Rockingstone Avenue, Larchmont, NY 10538 (US).
(74) Agents: RAYMOND, Robert, P. et al.; Boehringer Ingel-
heim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box
368. Ridgefield, , CT 06877 (US).
(81) Designated States (national): AE, AU, BG, BR, CA, CN,
CO, CZ, EC, EE, HR, HU, ID, IL, IN, JP, KR, LT, LV, MX,
NO, NZ, PL, RO, SG, SI, SK, UA, UZ, VN, YU, ZA.
(84) Designated States (regional): Eurasian patent (AM, AZ,
BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE,
CH, CY, DE, DK, ES, FL FR, GB, GR, IE, IT, LU, MC,
NL, PT, SE, TR).
Published:
— with international search report
For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at the begin-
ning of each regular issue of the PCT Gazette.
V©
is
O (54) Title: DIARYLUREA DERIVATIVES USEFUL AS ANTI-INFLAMMATORY AGENTS
(57) Abstract: Disclosed are diarylurea derivatives useful in pharmaceutic compositions for treating diseases or pathological con-
ditions involving inflammation such as chronic inflammatory diseases. Also disclosed are processes of making such compounds.
WO 02/092576
PCT/US02/14733
DIARYLUREA DERIVATIVES USEFUL AS ANTI— INFLAMMATORY AGENTS
APPLICATION DATA
This application claims benefit to US provisional application no. 60/291,425 filed May
16, 2001.
TECHNICAL FIELD OF THE TNVP.NTTON
This invention relates to novel compounds which possess anticytokine activity. The
compounds of the invention are thus useful for treating diseases and pathological
conditions involving inflammation such as chronic inflammatory disease. This invention
also relates to processes for preparing these compounds and to pharmaceutical
compositions comprising these compounds.
BACKGROUND OF TFTR INVENTION
Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are important biological entities
collectively referred to as proinflammatory cytokines. These, along with several other
related molecules, mediate the inflammatory response associated with the immunological
recognition of infectious agents. The inflammatory response plays an important role in
limiting and controlling pathogenic infections.
Elevated levels of proinflammatory cytokines are also associated with a number of
diseases of autoimmunity such as toxic shock syndrome, rheumatoid arthritis,
osteoarthritis, diabetes and inflammatory bowel disease (Dinarello, C.A., et al, 1984,
Rev. Infect. Disease 6.5\). In these diseases, chronic elevation of inflammation
exacerbates or causes much of the pathophysiology observed. For example, rheumatoid
synovial tissue becomes invaded with inflammatory cells that result in destruction to
cartilage and bone (Koch, A.E., et al, 1995, J. Invest. Med. 43: 28-38). Studies suggest
that inflammatory changes mediated by cytokines may be involved in the pathogenesis of
restenosis after percutaneous transluminal coronary angioplasty (PTCA) (Tashiro, H., et
<Ss_
WO 02/092576 PCT/US02/14733
al, 2001 Mar, Cor on Artery Dis 1 2(2): 107- 13). An important and accepted therapeutic
approach for potential drug intervention in these diseases is the reduction of
proinflammatory cytokines such as TNF (also referred to in its secreted cell-free form as
TNFa) and IL-1 p. A number of anti-cytokine therapies are currently in clinical trials.
5 Efficacy has been demonstrated with a monoclonal antibody directed against TNFa in a
number of autoimmune diseases (Heath, P., "CDP571: An Engineered Human IgG4 Anti-
TNFcc Antibody" BBC Meeting on Cytokine Antagonists, Philadelphia, PA, April 24-5,
1997). These include the treatment of rheumatoid arthritis, Crohn's disease and
ulcerative colitis (Rankin, E.C.C., et al., 1997, British J. Rheum. 35: 334-342 and Stack,
10 W.A., et al., 1997, Lancet 349: 52 1-524). The monoclonal antibody is thought to
function by binding to both soluble TNFa and to membrane bound TNF.
A soluble TNFa receptor has been engineered that interacts with TNFa. The approach is
similar to that described above for the monoclonal antibodies directed against TNFa;
15 both agents bind to soluble TNFa, thus reducing its concentration. One version of this
construct, called Enbrel (Immunex, Seattle, WA) recently demonstrated efficacy in a
Phase IH clinical trial for the treatment of rheumatoid arthritis (Brower et al, 1997,
Nature Biotechnology 15: 1240). Another version of the TNFa receptor, Ro 45-2081
(Hoffman-LaRoche Inc., Nutley, NJ) has demonstrated efficacy in various animal models
20 of allergic lung inflammation and acute lung injury. Ro 45-2081 is a recombinant
chimeric molecule constructed from the soluble 55 kDa human TNF receptor fused to the
hinge region of the heavy chain IgGl gene and expressed in eukaryotic cells (Renzetti, et
al, 1997, Inflamm. Res. 46: S143).
25 IL-1 has been implicated as an immunological effector molecule in a large number of
disease processes. IL-1 receptor antagonist (IL-lra) had been examined in human
clinical trials. Efficacy has been demonstrated for the treatment of rheumatoid arthritis
(Antril, Amgen). In a phase DI human clinical trial IL-lra reduced the mortality rate in
patients with septic shock syndrome (Dinarello, 1995, Nutrution 11, 492). Osteoarthritis
30 is a slow progressive disease characterized by destruction of the articular cartilage. IL-1
is detected in synovial fluid and in the cartilage matrix of osteoarthritic joints.
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WO 02/092576 PCT/US02/14733
Antagonists of IL-1 have been shown to diminish the degradation of cartilage matrix
components in a variety of experimental models of arthritis (Chevalier, 1997, Biomed
Pharmacother. 51, 58). Nitric oxide (NO) is a mediator of cardiovascular homeostasis,
neurotransmission and immune function; recently it has been shown to have important
5 effects in the modulation of bone remodeling. Cytokines such as EL-1 and TNF are
potent stimulators of NO production. NO is an important regulatory molecule in bone
with effects on cells of the osteoblast and osteoclast lineage (Evans, et al, 1996, J Bone
Miner Res. 11, 300). The promotion of beta-cell destruction leading to insulin dependent
diabetes mellitus shows dependence on IL-1. Some of this damage may be mediated
10 through other effectors such as prostaglandins and thromboxanes. IL-1 can effect this
process by controlling the level of both cyclooxygenase II and inducible nitric oxide
synthetase expression (McDaniel et al., 1996, Proc Soc Exp Biol Med. 211, 24).
Inhibitors of cytokine production are expected to block inducible cyclooxygenase (COX-
15 2) expression. COX-2 expression has been shown to be increased by cytokines and it is
believed to be the isoform of cyclooxygenase responsible for inflarnmation (M.K.
O'Banion et al, Proc. Natl. Acad. Sci.U.S.A, 1992, 89, 4888.) Accordingly, inhibitors of
cytokines such as IL-1 would be expected to exhibit efficacy against those disorders
currently treated with COX inhibitors such as the familiar NSAIDs. These disorders
20 include acute and chronic pain as well as symptoms of inflammation and cardiovascular
disease.
Elevation of several cytokines have been demonstrated during active inflammatory bowel
disease (EBD). A mucosal imbalance of intestinal IL-1 and IL-lra is present in patients
25 with EBD. Insufficient production of endogenous EL-lra may contribute to the
pathogenesis of EBD (Cominelli, et al, 1996, Aliment Pharmacol Ther. 10, 49).
Alzheimer disease is characterized by the presence of beta-amyloid protein deposits,
neurofibrillary tangles and cholinergic dysfunction throughout the hippocampal region.
The structural and metabolic damage found in Alzheimer disease is possibly due to a
30 sustained elevation of EL-1 (Holden, et al, 1995, Med Hypotheses, 45, 559). A role for
EL-1 in the pathogenesis of human immunodeficiency virus (HIV) has been identified.
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IL-lra showed a clear relationship to acute inflammatory events as well as to the different
disease stages in the pathophysiology of HIV infection (Kreuzer, et al, 1997, Clin Exp
Immunol. 109, 54). IL-1 and TNF are both involved in periodontal disease. The
destructive process associated with periodontal disease may be due to a deregulation of
both IL-1 and TNF (Howells, 1995, OralDis. 1, 266).
Proinflammatory cytokines such as TNFa and IL-1 p are also important mediators of
septic shock and associated cardiopulmonary dysfunction, acute respiratory distress
syndrome (ARDS) and multiple organ failure. In a study of patients presenting at a
hospital with sepsis, a correlation was found between TNFa and IL-6 levels and septic
complications (Terregino et al., 2000, Ann. Emerg. Med., 35, 26). TNFa has also been
implicated in cachexia and muscle degradation, associated with HTV infection
(Lahdiverta et al, 1988, Amer. J. Med., 85, 289). Obesity is associated with an increase
incidence of infection, diabetes and cardiovascular disease. Abnormalities in TNFa
expression have been noted for each of the above conditions (Loffreda, et al, 1998,
FASEB J. 12, 57). It has been proposed that elevated levels of TNFa are involved in
other eating related disorders such as anorexia and bulimia nervosa. Pathophysiological
parallels are drawn between anorexia nervosa and cancer cachexia (Holden, et al., 1996,
Med Hypotheses 47, 423). An inhibitor of TNFa production, HU-21 1, was shown to
improve the outcome of closed brain injury in an experimental model (Shohami, et al,
\991,JNeuroimmunol. 72, 169). Atherosclerosis is known to have an inflammatory
component and cytokines such as IL-1 and TNF have been suggested to promote the
disease. In an animal model an IL-1 receptor antagonist was shown to inhibit fatty streak
formation (Elhage et al, 1998, Circulation, 97, 242).
TNFa levels are elevated in airways of patients with chronic obstructive pulmonary
disease and it may contribute to the pathogenesis of this disease (M.A. Higham et al,
2000, Eur. Respiratory J., 15, 281). Circulating TNFa may also contribute to weight loss
associated with this disease (N. Takabatake et al, 2000, Amer. J. Resp. & Crit. Care
Med., 161 (4 Pt 1), 1 179). Elevated TNFa levels have also been found to be associated
with congestive heart failure and the level has been correlated with severity of the disease
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(A.M. Feldman et al, 2000, J. Amer. College of Cardiology, 35, 537). In addition, TNFa
has been implicated in reperfusion injury in lung (Borjesson et al, 2000, Amer. J.
Physiol, 278, L3-12), kidney (Lemay et al., 2000, Transplantation, 69, 959), and the
nervous system (Mitsui et al, 1999, Brain Res., 844, 192).
TNFa is also a potent osteoclastogenic agent and is involved in bone resorption and
diseases involving bone resorption (Abu-Amer et al, 2000, J. Biol Chem., 275, 27307).
It has also been found highly expressed in chondrocytes of patients with traumatic
arthritis (Melchiorri et al, 2000, Arthritis and Rheumatism, 41, 2165). TNFa has also
been shown to play a key role in the development of glomerulonephritis (Le Hir et al,
1998, Laboratory Investigation, 78, 1625).
The abnormal expression of inducible nitric oxide synthetase (iNOS) has been associated
with hypertension in the spontaneously hypertensive rat (Chou et al, 1998, Hypertension,
31, 643). EL-1 has a role in the expression of iNOS and therefore may also have a role in
the pathogenesis of hypertension (Singh et al., 1996, Amer. J. Hypertension, 9, 867).
IL-1 has also been shown to induce uveitis in rats which could be inhibited with IL-1
blockers. (Xuan et al., 1998, J. Ocular Pharmacol and Ther., 14, 3 1). Cytokines
including IL-1, TNF and GM-CSF have been shown to stimulate proliferation of acute
myelogenous leukemia blasts (Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown
to be essential for the development of both irritant and allergic contact dermatitis.
Epicutaneous sensitization can be prevented by the administration of an anti- EL-1
monoclonal antibody before epicutaneous application of an allergen (Muller, et al, 1996,
Am J Contact Dermal 7, 177). Data obtained from IL-1 knock out mice indicates the
critical involvement in fever for this cytokine (Kluger et al, 1998, Clin Exp Pharmacol
Physiol 25, 141). A variety of cytokines including TNF, IL-1, IL-6 and IL-8 initiate the
acute-phase reaction which is stereotyped in fever, malaise, myalgia, headaches, cellular
hypermetabolism and multiple endocrine and enzyme responses (Beisel, 1995, Am J Clin
Nutr. 62, 813). The production of these inflammatory cytokines rapidly follows trauma
or pathogenic organism invasion.
WO 02/092576
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Other proinflammatory cytokines have been correlated with a variety of disease states.
EL-8 correlates with influx of neutrophils into sites of inflammation or injury. Blocking
antibodies against EL-8 have demonstrated a role for IL-8 in the neutrophil associated
tissue injury in acute inflammation (Harada et al, 1996, Molecular Medicine Today 2,
482). Therefore, an inhibitor of IL-8 production may be useful in the treatment of
diseases mediated predominantly by neutrophils such as stroke and myocardial infarction,
alone or following thrombolytic therapy, thermal injury, adult respiratory distress
syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis,
dermatoses with acute inflammatory components, acute purulent meningitis or other
central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion
associated syndromes, and necrotizing enterocolitis.
Rhinovirus triggers the production of various proinflammatory cytokines, predominantly
IL-8, which results in symptomatic illnesses such as acute rhinitis (Wintrier et al, 1998,
AmJBhinol. 12,11).
Other diseases that are effected by IL-8 include myocardial ischemia and reperfusion,
inflammatory bowel disease and many others.
The proinflammatory cytokine LL-6 has been implicated with the acute phase response.
IL-6 is a growth factor in a number in oncological diseases including multiple myeloma
and related plasma cell dyscrasias (Treon, et al, 1998, Current Opinion in Hematology 5:
42). It has also been shown to be an important mediator of inflammation within the
central nervous system. Elevated levels of IL-6 are found in several neurological
disorders including AIDS dementia complex, Alzheimer's disease, multiple sclerosis,
systemic lupus erythematosus, CNS trauma and viral and bacterial meningitis (Gruol, et
al, 1997, Molecular Neurobiology 15: 307). IL-6 also plays a significant role in
osteoporosis. In murine models it has been shown to effect bone resorption and to induce
osteoclast activity (Ershler et al, 1997, Development and Comparative Immunol. 21:
487). Marked cytokine differences, such as IL-6 levels, exist in vivo between osteoclasts
of normal bone and bone from patients withPaget's disease (Mills, et al, 1997, Calcif
WO 02/092576 PCT/US02/14733
Tissue Int. 61, 16). A number of cytokines have been shown to be involved in cancer
cachexia. The severity of key parameters of cachexia can be reduced by treatment with
anti EL-6 antibodies or with IL-6 receptor antagonists (Strassmann, et al, 1995, Cytokins
Mol Ther. 1, 107). Several infectious diseases, such as influenza, indicate IL-6 and IFN
5 alpha as key factors in both symptom formation and in host defense (Hayden, et al,
1998, J Clin Invest. 101, 643). Overexpression of IL-6 has been implicated in the
pathology of a number of diseases including multiple myeloma, rheumatoid arthritis,
Castleman's disease, psoriasis and post-menopausal osteoporosis (Simpson, et al, 1997,
Protein Sci. 6, 929). Compounds that interfered with the production of cytokines
10 including IL-6, and TNF were effective in blocking a passive cutaneous anaphylaxis in
mice (Scholz et al, 1998, J. Med. Chem., 41, 1050).
GM-CSF is another proinflammatory cytokine with relevance to a number of therapeutic
diseases. It influences not only proliferation and differentiation of stem cells but also
15 regulates several other cells involved in acute and chronic inflammation. Treatment with
GM-CSF has been attempted in a number of disease states including burn- wound healing,
skin-graft resolution as well as cytostatic and radiotherapy induced mucositis (Masucci,
1996, Medical Oncology 13: 149). GM-CSF also appears to play a role in the replication
of human immunodeficiency virus (HTV) in cells of macrophage lineage with relevance
20 to AIDS therapy (Crowe et al, 1997, Journal of Leukocyte Biology 62, 41). Bronchial
asthma is characterised by an inflammatory process in lungs. Involved cytokines include
GM-CSF amongst others (Lee, 1998, JR Coll Physicians Lond 32, 56).
Interferon y (IFN y) has been implicated in a number of diseases. It has been associated
25 with increased collagen deposition that is a central histopathological feature of graft-
versus-host disease (Parkman, 1998, Curr Opin Hematol. 5, 22). Following kidney
transplantation, a patient was diagnosed with acute myelogenous leukemia.
Retrospective analysis of peripheral blood cytokines revealed elevated levels of GM-CSF
and IFN y. These elevated levels coincided with a rise in peripheral blood white cell
30 count (Burke, et al, 1995, Leuk Lymphoma. 19, 173). The development of insulin-
dependent diabetes (Type 1) can be correlated with the accumulation in pancreatic islet
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cells of T-cells producing IFN y (Ablumunits, et al, 1998, JAutoimmun. 11, 73). IFNy
along with TNF, IL-2 and IL-6 lead to the activation of most peripheral T-cells prior to
the development of lesions in the central nervous system for diseases such as multiple
sclerosis (MS) and AIDS dementia complex (Martino et al, 1998, Ann Neurol. 43, 340).
Atherosclerotic lesions result in arterial disease that can lead to cardiac and cerebral
infarction. Many activated immune cells are present in these lesions, mainly T-cells and
macrophages. These cells produce large amounts of proinflammatory cytokines such as
TNF, IL-1 and IFN y. These cytokines are thought to be involved in promoting apoptosis
or programmed cell death of the surrounding vascular smooth muscle cells resulting in
the atherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76). Allergic subjects
produce mRNA specific for IFN y following challenge with Vespula venom (Bonay, et
al, 1997, Clin Exp Immunol. 109, 342). The expression of a number of cytokines,
including IFN y has been shown to increase following a delayed type hypersensitivity
reaction thus indicating a role for IFN y in atopic dermatitis (Szepietowski, et al., 1997,
Br J Dermatol. 137, 195). Histopathologic and immunohistologic studies were
performed in cases of fatal cerebral malaria. Evidence for elevated IFN y amongst other
cytokines was observed indicating a role in this disease (Udomsangpetch et al., 1997, Am
J Trop MedHyg. 57, 501). The importance of free radical species in the pathogenesis of
various infectious diseases has been established. The nitric oxide synthesis pathway is
activated in response to infection with certain viruses via the induction of
proinflammatory cytokines such as IFN y (Akaike, et al., 1998, Proc Soc Exp Biol Med.
21 7, 64). Patients, chronically infected with hepatitis B virus (HBV) can develop
cirrhosis and hepatocellular carcinoma. Viral gene expression and replication in HBV
transgenic mice can be suppressed by a post-transcriptional mechanism mediated by IFN
y, TNF and IL-2 (Chisari, et al, 1995, Springer Semin Immunopathol 1 7, 261). IFN y
can selectively inhibit cytokine induced bone resorption. It appears to do this via the
intermediacy of nitric oxide (NO) which is an important regulatory molecule in bone
remodeling. NO may be involved as a mediator of bone disease for such diseases as: the
rheumatoid arthritis, tumor associated osteolysis and postmenopausal osteoporosis
(Evans, et al, 1996, J Bone Miner Res. 11, 300). Studies with gene deficient mice have
demonstrated that the EL- 12 dependent production of IFN y is critical in the control of
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early parasitic growth. Although this process is independent of nitric oxide the control of
chronic infection does appear to be NO dependent (Alexander et al, 1997, Philos Trans
R Soc Lond B Biol Sci 352, 1355). NO is an important vasodilator and convincing
evidence exists for its role in cardiovascular shock (Kilbourn, et al, 1997, Dis Mon. 43,
277). IFN y is required for progression of chronic intestinal inflammation in such
diseases as Crohn's disease and inflammatory bowel disease (IBD) presumably through
the intermediacy of CD4+ lymphocytes probably of the TH1 phenotype (Sartor 1996,
Aliment Pharmacol Ther. 10 Suppl 2, 43). An elevated level of serum IgE is associated
with various atopic diseases such as bronchial asthma and atopic dermatitis. The level of
IFN y was negatively correlated with serum IgE suggesting a role for IFN y in atopic
patients (Teramoto et al, 1998, Clin Exp Allergy 28, 74).
WO 01/01986 discloses particular compounds alleged to having the ability to inhibit
TNF-alpha. The specific inhibitors disclosed are structurally distinct from the novel
compounds disclosed in the present application disclosed hereinbelow. Certain
compounds disclosed in WO 01/01986 are indicated to be effective in treating the
following diseases: dementia associated with HTV infection, glaucoma, optic-neuropathy,
optic neuritis, retinal ischemia, laser induced optic damage, surgery or trauma-induced
proliferative vitreoretinopathy, cerebral ischemia, hypoxia-ischemia, hypoglycemia,
domoic acid poisoning, anoxia, carbon monoxide or manganese or cyanide poisoning,
Huntington's disease, Alzheimer's disease, Parkinson's disease, meningitis, multiple
sclerosis and other demyelinating diseases, amyotrophic lateral sclerosis, head and spinal
cord trauma, seizures, convulsions, olivopontocerebellar atrophy, neuropathic pain
syndromes, diabetic neuropathy, HTV-related neuropathy, MERRF and MELAS
syndromes, Leber's disease, Wernicke's encephalophathy, Rett syndrome,
homocysteinuria, hyperprolinemia, hyperhomocystememia, nonketotic hyperglycinemia,
hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease,
lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug
tolerance, drug dependency, depression, anxiety and schizophrema.
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Compounds which modulate release of one or more of the aforementioned inflammatory
cytokines can be useful in treating diseases associated with release of these cytokines. For
example, WO 98/52558 discloses heteroaryl urea compounds which are indicated to be
useful in treating cytokine mediated diseases. WO 99/23091 discloses another class of
urea compounds which are useful as anti-inflammatory agents. WO 99/32463 relates to
aryl ureas amd their use in treating cytokine diseases and proteolytic enzyme mediated
disease. WO 00/41698 discloses aryl ureas said to be useful in treating p38 MAP kinase
diseases.
U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N'-heterocyclic substituted urea
compounds which are described as being useful for treating hypercholesterolemia and
atheroclerosis.
The work cited above supports the principle that inhibition of cytokine production will be
beneficial in the treatment of various disease states. Some protein therapeutics are in late
development or have been approved for use in particular diseases. Protein therapeutics
are costly to produce and have bioavailability and stability problems. Therefore a need
exists for new small molecule inhibitors of cytokine production with optimized efficacy,
pharmacokinetic and safety profiles.
BRIEF SUMMARY OF THE INVENTION
The work cited above supports the principle that inhibition of cytokine production will be
beneficial in the treatment of various disease states.
It is therefore an object of the invention to provide novel compounds which inhibit the
release of inflammatory cytokines such as mterleukin-1 and tumor necrosis factor.
It is a further object of the invention to provide methods for treating diseases and
pathological conditions involving inflammation such as chronic inflammatory disease,
using the novel compounds of the invention.
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It is yet a further object of the invention to provide processes of preparation of the above-
mentioned, novel compounds.
DETAILED DESCRIPTION OF THE TNVFNTTON
In a first embodiment, the invention provides the following compounds:
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-isopropyl-6-methyl-
„ /wOv^i^ pvrimidin-4-yloxy)-naphthalen-l-yl]-urea;
l-(5-tert-Butyl-2-memoxy-phenyl)-3-[4-(2,6-dmiemyl-pyrimidin-
Vv 4-yloxy)~naphthalen-l-yl]-urea;
l-(5-tert-Bu1yl-2-methoxy-phenyl)-3-[4-(pyrinndin-4-yloxy)-
v^,n naphthalen-l-yl]-urea;
l-CS-tert-Butyl^-methoxy-S-Cl^^triazoM-yl-phenyl)^-^-
(pyrimidin-4-yloxy)-naphthalen-l-yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-oxo-2H-pyran-4-
yloxy)-naphuialen-l-yl]-urea;
5-tert-Butyl-2-memoxy-3-{3-[4-(6-morpholin-4-ylmemyl-pyridin-
3 -yl)-naphthalen- 1 -yl]-ureido} -b enzoic acid;
"^Y^ ^jOOQ C ^ bo ^ cacid5 - tert - but y 1 - 2 - meth o x y-3-{3-[4-(6-morphohn-4-
JiJJkJijCk/ ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-ureido}-phenyl ester
I methyl ester;
11
PCT/US02/14733
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-isopropylamino-
■°Y Nj Y NH [ 1 > 3 » 5 ] tri azin-2-yloxy)-naphthaleii-l-yl]-urea;
A l-(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[4-(cyclopropylmethyl-
.^n^h ainino)-[13 > 5]triazin-2-yloxy]-naphthalen-l-yl}-urea;
u 0
l_[4.(4_Amino-[l,3,5]triazin-2-yloxy)-naphthalen-l-yl]-3-(5-tert-
°-Y n <y nh ' bu tyl-2-methoxy-phenyl)-urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3-[4-([ 1 ,3,5]triazin-2-yloxy)-
, -o^-n^ naphtfaalen-l-yl]-urea;
y 1 -(5-tert-Butyl-2-methoxy-phenyl)-3 -[4-(2-cyclopropylamino-6-
jj^V°Y H T H me ^y 1 "Py i ^<iin-4-yloxy)-iiaphthalen-l-yl]-xirea;
ft
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-methylamino-
o-y-'W-'S, pyriirridin-4-yloxy)-naphthalen- 1 -yl]-urea;
f l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-etiiylamino-pyriiiudin-
Vy^H 4-yloxy)-naphthalen-l-yl]-urea;
, l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-methyl-2-
jTY°T N ^ NH me& y la ^°-Py^ d ^- 4 -y lox y)- na Phthalen-l-yl]-urea;
1 -[4-(2-Amino-6-me1iiyl-pyriiEidin-4-yloxy)-naphthalen- 1 -yl]-3-
Y NH ' (5-tert-butyl-2-methoxy-phenyl)-\irea;
,0. K-.NH,
Hi l-[4-(2-Amino-pyrimidin^-yloxy)-naphthalen-l-yl]-3-(5-tert-
X XX * butyl-2-methoxy-phenyl)-xirea;
12
PCT/US02/14733
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-cyclopentylamino-
pyrimidin-4-yloxy)-naphthalen- 1 -yl]-urea;
A. 1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(cyclopropylmethyl-
o^^J^ aiiiino)-pyrimidin-4-yloxy]-naplathalen-l-yl}-urea;
A. 1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(cyclopropylmethyl-
%-% aj ^°)" 6-me ^yl-py j ^^ n -^yloxy]-iiaphtlialeri-l-yl}-iirea;
X.
<Qf l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4- {2-.[(tetrahydro-furan-2-
y y lmeth y0-amino]-pyrimidin-4-yloxy} -naphthalen- 1 -yl)-urea;
Qf l<5-tert-Butyl-2-methoxy-phenyl)-3<4-{2-[(pyridin-2-ylmethyl)-
Jl' ^ino]-pyrimidin-4-yloxy}-naphthalen-l-yl)-urea;
0 l-(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(2-morpholin-4-yl-
ethylaiiiino)-pyrimidin-4-yloxy]-iiaphtiialen-l-yl}-xirea;
Qi l-[4-(2-Ben2ylamino-pyrimidia-4-yloxy)-naphthaleii-l-yl]-3-(5-
Ti tert-butyl-2-methoxy-phenyl)-urea;
I 1 -[4-(2-sec-Butylamino-pyrimidin-4-yloxy)-naplithaleii- 1 -yl]-3-
o^-NvJiC, (5-tert-butyl-2-methoxy-phenyl)-urea;
XX
> l-(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(2-methoxy-
« eth y laj ^°)-pyri«udin-4-yloxy]-iiaphthalen- 1 -yl} -urea;
< l-(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(2-dimethylamino-
]. ethylamino)-pyriiiiidin-4-yloxy]-naphthalen- 1 -yl} -urea;
13
PCT/US02/14733
1 1_ ( 5 - te ^; B V^ 2 - me&ox y-P hen y^- 3 -[4<2-dime%lainino-
Y N Pyrimidin-4-yloxy)-naphthalen- 1 -yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-pyiroUdin-l-yl-
^^K/ pyrimidin-4-yloxy)-naphttialeii- 1 -y l]-urea;
P* l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-methyl-2-pyrrolidin-l-
(r^Y 0 Y N -V N ^ y^Py^din-^-ylo^-naphthalen-l-yy-urea;
^ l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-moipholin-4-yl-
'^ s Y'~Y Ni Y' N Py rimidin - 4 -yloxy)-naplithalen-l-yl]-iirea;
I
l-(5-tert-ButyI-2-methoxy-phenyl)-3-{4-[2-(4-methyl-piperazin-
XY'O l-yl)-pyrimidin-4-yloxy]-naphthalen-l-yl}-urea;
^ l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-ethoxy-pyrimidin-4-
II yVt yIoxy)-naphthalen-l-yl]-urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(2-moipholin-4-yl-
ethoxy)-pyrimidin-4-yloxy]-naphthaIen-l-yl}-urea;
Y l-(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(2-dimethyl;
Q „~ .-vjO ^^"Py^^^-yloxyJ-naphthalen-l-yll-urea;
amino-
j) 1 -[ 4 -(2-Beri2ylamino-pyrimidin-4-yloxy)-naphthaleii-l-yl]-3-(5-
s tert-butyl-2-methoxy-3-[ 1 ,2,4]triazol-4-yl-phenyl)-urea;
H
1 -(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-methanesulfinyl-
^^Y° •y'V ° Py iMdil ^y lox y)- | « l PMbalen- 1 -yl]-urea;
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l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-methylsulfanyl-
°v^n 1 pyrimidin-4-yloxy)-naphthalen- 1 -yl]-urea;
ylmethyl-pyridin-3-yl)-naphthalen- 1 -yl]-urea;
JL
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(2-methoxy-phenyl)-
^QTT Pyrinudin-4-yIoxy]-naphthalen- 1 -yl} -urea;
a9
^ l-(5-t6rt-Butyl-2-methoxy-phenyl)-3-{4-[2-(3-methoxy-phenyl)-
^ jf^l^'^'i Py^f^din^-yloxyJ-naphthalen-l-yll-urea;
JL
l-(5-tert-Butyl-2-mefhoxy-phenyl)-3-[4-(2-phenyl-pyrimidin-4-
Y-'y^' yloxy)-naphthalen-l-yl]-urea;
4-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-tireido]-naphthalen-l-
^if^Tj* 0 yloxy}-pyrimidine-2-carbbxylic acid methyl ester;
°^Y° N yloxy)-naphthalen-l-yl]-urea;
l-(5-tert-Bu1yl-2-methoxy-phenyl)-3-[4-(2-cyano-pyrimidiri-4-
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(tetrahydro-pyran-4-
yloxy)-naphthalen- 1 -yl]-urea;
or the pharmaceutically acceptable derivatives thereof.
5 In a second embodiment, the invention provides the following compounds:
r-N. 1 -[5-tert-Butyl-3 -(1,1 -dioxo- 1 -lambda-6-isotbiazolidin-2-yl)-2-
- -° methoxy-phenyl]-3-[4-(6-morpholm-4-ylmemyl-pyridin-3-yl)-
naphthalen- 1 -yl]-urea;
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°>.o
N-(3-{3-[4-(2-Amino-6-methyl-pyrinudin^-yloxy)-naphthaIen-l
• N r NH ' yl]-uxeido} -5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide
N-(3-{3-[4-(2-Ainino-pyrimidin-4-yloxy)-naphthalen-l-yl]-
0 ^^- NH ' ureido} -5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide;
N CN N_ ( 5_tert - Bu ^ 1 - 3 -{ 3 -[ 4 K2-cyano-pyrimidin-4-yloxy)-naphthalen
"iQf 1 -yl]-ureido} -2-metboxy-phenyl)-methanesulfonamide;
Y o N -( 5 - te rt-Butyl-2-methoxy-3-{3-[4-(tetrahydropyran-4-yloxy)-
I JpL^-l^XXj na P hthalen " 1 -yl]-ureido} -phenyl)-methanesulfonamide
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(pyrimidin-4-yloxy)-
^ naphthalen- 1 -ylj-ureido} -phenyl)-methanesulfonamide;
NK5-tert-Butyl-2-methoxy-3-{3-[4-(2-methylamino-pyriiiiidin-4-
h yloxy)-naphtlialen-l-yl]-ureido}-phenyl)-methanesulfonamide;
N-(5-tert-Butyl-2-metJioxy-3-{3-[4-(6-methyl-2-niethylamino-
pyrimidin-4-yloxy)-naphtiialen-l-yl]-ureido}-phenyl)-
methanesulfonamide;
N-[54ert-Butyl^-(3-{4-[2-(cyclopropylmeliyl-amiiio)-pyrimidin-
i. H 4-yloxy]-naphthalen- 1 -yl} -ureido)-2-methoxy-phenyl]-
methanesulfonamide;
N-[5-tert-Butyl-3 -(3- {4-[2-(cyclopropylmethyl-amino)-6-methyl-
pyrimidin-4-yloxy]-naphthalen-l-yl}-ureido)-2-methoxy-phenyl]-
methanesulfonamide;
N-{5-tert-Butyl-2-methoxy-3-[3-(4-{2-[(tetrahydro-ftiran-2-
ylmethyl)-amino]-pyrimidin^-^^^
phenyl} -methanesulfonamide;
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N-(5-tert-Butyl-2-methoxy-3-{3-[4<2-pyiroUdin-l-yI-pyrimidin
4-yloxy)-naphthalen- 1 -yl]-ureido} -phenyl)-methanesulfonarnide
or the phannaceutically acceptable derivatives thereof.
In a third embodiment, the invention provides the following compounds:
1 -[5-tert-butyl-2-(2-hydroxy-4-methyl-phenyl)-2H-pyrazol-3-yl]
vj> 3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l -yl]-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-{4-[2-
(hydroxy)ethoxy]-naphthalen- 1 -yl} -urea;
1 -[ 5 - tert - but yl-2-p-tolyl-2H-pyrazol-3-yl]-3-{4-[2-oxo-2-
l^J, (morpholin-4-yl)-ethoxy]-naphthalen- 1 -yl } -urea;
~t^v n rr^r- 0H 1 -C 5 - tert - but y I - 2 -P-tolyl-2H-pyrazol-3-yl]-3-{4-[hydroxyl-
"N^H-^H ^SrS naphthalen-l-yl}-urea
or the phannaceutically acceptable derivatives thereof.
In a fourth embodiment, the invention provides the following compounds which can be
made be the procedures illustrated in the General Synthetic Methods and Experimental
sections provided herein below:
1 -(5-tert-Butyl-2-memoxy-phenyl)-3-[4-(2-isopropylamino-
vj£^n.. h pyrimidin-4-yloxy)-naphthalen-l-yl]-urea;
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PCT/US02/14733
V l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-cyclopropylamino-
^n^ h pyrimidin-4-yloxy)-naphthalen-l -yl]-urea;
^ l-(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(l-phenyl-
^ etiiylaniino)-pyriiiii(iin-4-yloxy]-naphtiialen- 1 -yl} -urea;
v l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{2-[(pyridin-3-ylmethyl)-
"'•Y'V'' 4 — ^^ ai ^o]-py r ^d^-^yloxy}-naphthalen-l-yl)-urea;
iji f^u l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{2-[(pyridin-4-ylmethyl)-
'v^^i^A^ amino]-pyrinudin^-yloxy}-naphthalen-l-yl)-virea;
X l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{2-[2-(4-methyl-
1 piperazin- 1 -yl)-ethylamiiio]-pyrimidin-4-yloxy } -naphthalen- 1 -
'^jX yl)-urea;
Q l-(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(2-pyrrolidin-l-yl-
ethylamino)-pyrimidin-4-yloxy]-naphtiialeii-l-yl}-iirea;
(~3^ o l-(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(2-oxo-tetrahydro-
Y furan-3-ylainino)-pyrinudin^-yloxy]-naphthalen-l-yl}-iirea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(tetrahydro-furan-3-
k ylamino)-pyrimidin-4-yloxy]-naphthalen- 1 -yl} -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-methyl-2-[(tetrahydro-
furan-2-ylmethyl)-amino]-pyrimidin-4-yloxy} -naphthalen- 1 -yl)-
I urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(2-methoxy-l -methyl-
^ e&ylamino)-pyrimidin-4-yloxy]-naphtiialen- 1 -yl} -urea;
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v" 2-(4- {4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphtlialen-
l-yloxy}-pyrinudin-2-ylamino)-propionamide;
V" 2-(4-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-
JJ^X' 1 -yloxy} -pyrimidin-2-ylamino)-N-methyl-propionamide;
2-(4- {4-[3-(5-tert-B-utyl-2-methoxy-phenyl)-ureido]-naphthalen-
T\ 1 -yloxy} -pyrimidin-2-ylamino)-N,N-dimethyl-propionamide;
I 1 J
2-(4- {4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-
£JL 1 ~y lox y } -pyriinidin-2-ylamino)-N,N-dimethy l-acetemide
l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{2-[l-(3-methoxy-
kX^ phenyl)-ethylamino]-pyrimidin-4-yloxy}-naphthalen- 1 -yl)-urea;
|fY* 1 -(4- {2-[ 1 -(2-Bromo-phenyl)-ethylainino]-pyriiiudin-4-yloxy } -
naphthalen-l-yl)-3-(5-tert-butyl-2-methoxy-phenyl)-iirea;
IJ l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(4-diethylamino-l-
methyI-butylamino)-pyriinidin-4-yloxy]-naphthalen-l-yl}-urea;
°l£X l-(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(4-methoxy-
0 Tj, ben2ylamino)-pyrimidin-4-yloxy]-naphthalen-l-yl}-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(3-chloro-
benzylamino)-pyrimidin-4-yloxy]-naphthalen-l -yl} -urea;
1 - {4-[2-(Beiozyl-me1^yl-airuno)-pyrimidin-4-yloxy] -naphthalen-
l-yl}-3-(5-tert-butyl-2-metb.oxy-pb.enyl)-urea;
XX "
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Y 1 -(5-tert-Butyl-2-methoxy-phenyl)-3-(4- {2-[(2-dimethylamino-
1 ethyl)-me%l-amino]-pyrimidin^^
^oJXj> yy-S-CS-tert-butyl^-methoxy-phenyO-urea;
j T TY "
Ql 1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[6-methyl-2-( 1 -phenyl-
Tjf ethylainino)-pyriinidin-4-yloxy]-naphthalen-l-yl}-urea;
Qf l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4- {6-methyl-2-[(pyridin-2-
■oSXDi y^ e ^yD-amino]-pyrimidin-4-yloxy> -naphthalen- 1 -yl)-urea;
'<T l-(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(2-dimethylamino-
yl^, e ^y la ^°)- 6 - me t h y 1 -pyi^^^-yloxy]-naphthalen-l-yl}-urea;
O H5-tert-Butyl-2-methoxy-phenyl)-3- {4-[6-methyl-2-(2-
C moipholin^-yl-ethylamino)-pyrimidin-4-yloxy]-naphthalen-l-
l-(5-tert-Butyl-2-metiioxy-phenyl)-3-[4-(2-diinethylamino-6-
^Y-n^ methyl-pyrimidin-4-yloxy)-naphthalen- l-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3- {3-[4-(2-morpholin-4-yl-pyrimidin-
'-^y-^ 4-yloxy)-naphthalen- 1 -yl]-ureido} -phenyl)-methanesulfonamide;
Q) N-[5-tert-Butyl-2-methoxy-3-(3-{4-[2-(l-phenyl-ethylamino)-
, 0 /XX Py^^^-yioxyl-naplithalen-l-yll-ureidoJ-phenyl]-
TI methanesulfonamide;
N-[5-tert-Butyl-2-methoxy-3-(3-{4-[6-methyl-2-(l-phenyl-
ethylamino)-pyrimidin^-yloxy]-naphthalen-l-yl}-iireido)-
' T phenylj-methanesulfonamide;
20
PCT/US02/14733
N- {5-tert-Butyl-2-methoxy-3-[3-(4- {2-[(pyridin-3-ylmethyl)-
ammo]-pyriniidin-4-yloxy} -naphthalen- 1 -yl)-ureido]-phenyl} -
H methanesulfonamide;
-T N-[5-tert-Butyl-3-(3-{4-[2<2-dimethylaiiiino-ethylamiiio)-
pyninidin-4-yloxy]-naphthalen-l-yl}-ureido)-2-methoxy-phenyl]-
J methanesulfonamide;
V N-[5-tert-Butyl-3-(3- {4-[2-(2-dimemylammo-ethylamino)-6-
1 memyl-pyrirmdm^-yloxy]-naphthalen-l-yl}-ureido)-2-methoxy-
phenylj-memanesulfonamide;
Q N-[5-tert-Butyl-2-methoxy-3-(3- {4-[2-(2-morpholin-4-yl-
k emylammo)-pyriinidin-4-yloxy]-naphthalen- 1 -yl} -ureido)-
^XjJXX P* 1 ^ 1 ] -methanesulfonamide;
N-[5-tert-Butyl-2-methoxy-3-(3-{4-[6-methyl-2-(2-moipholin-4-
yl-emylamino)-pyrimidin-4-yloxy]-naphthalen- 1 -yl} -ureido)-
phenyl] -methanesulfonamide;
, N-(5-tert-Butyl-3- {3-[4-(2-dimemylaniino-pyrimidin-4-yloxy)-
VV N " na P htliale n-l-yl]-ureido}-2-methoxy-phenyl)-
^ N methanesulfonamide;
N-[5-tert-Butyl-2-methoxy-3-(3-{4-[2-(4-methyl-piperazin-l-yl)-
pyrinTidin-4-yloxy]-naphthalen-l-yl}-ureido)-phenyl]-
methanesulfonamide:
N-(5-tert-Butyl-2-methoxy-3- {3-[4-(2-piperidin-l -yl-pyrimidin-4
N ^ yloxy)-naphthalen-l-yl]-ureido}-phenyl)-methanesulfonamide;
"T N -{ 5 -tert-Butyl-3-[3-(4-{2-[(2-dimethylamino-ethyl)-methyl
^ amino]-pyrimidin-4-yloxy}-naphthalen-l-yl)-ureido]-2-meth
phenyl} -methanesulfonamide;
•methoxy-
N^5-tert-Butyl-2-methoxy-3-(3-{4-[2-(tetrahydrofuran-3-
ylamino)-pyrinudin-4-yloxy]-naphthalen- 1 -yl} -ureido)-phenyll-
methanesulfonamide;
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PC17US02/14733
V
N-[5-tert-Butyl-2-methoxy-3 -(3 - {4-[2-(2-methoxy- 1 -methyl-
ethylainino)-pyrimidin-4-yloxy]-naphthalen- 1 -yl} -ureido)-
phenyl] -methanesulf onamide;
2-(4-{4-[3-(5-tert-Butyl-3-methanesidfonylamiiio-2-methoxy-
'^Y phenyl)-iireido]-naphthalen-l-yloxy}-pyrimidin-2-ylamino)-N-
methyl-propionamide;
2-(4-{4-[3-(5-tert-Butyl-3-methanesulfonylaiiiino-2-methoxy-
^^j,^ phenyl)-ureido]-naphthalen- 1 -yloxy } -pyrimidin-2-ylamino)-N,N-
iQT dimethyl-propionarnide;
N- {5-tert-Butyl-2-methoxy-3-[3-(4- {2-[(pyridin-2-ylmethyl>
, „ Vh amino]-pyrimidiii-4-yloxy } -naphthalen- 1 -yl)-ureido] -phenyl} -
^ H methanesulfonamide;
N- {5-tert-Butyl-2-methoxy-3-[3-(4- {6-methyl-2-[(tetrahydro-
\X„ ^ an_2 -y^ e ^y 1 )- aj ^o]-pyi^^^yloxy}-naphthalen-l-yl)-
i ureido]-phenyl}-me1hanesuifonamide;
^ N-(5-tert-Butyl-2-methoxy-3- {3-[4-(6-methyl-2-pyrrohdin-l-yl-
pyriinidin-4-yloxy)-naphthalen-l-yl]-ureido}-plienyl)-
methanesulfonamide;
2-(5-tert-Butyl-2-methoxy-3-{3-[4-(pyridin-4-yloxy)-naphthalen-
l-yl]-ureido}-phenylamino)-thiazole-4-carboxylic acid ethyl ester;
Q 2-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-pyrrolidin-l-ylmethyl-
pyridin-4-yloxy)-naphthalen-l-yl]-ureido}-pheaylamino)-
thiazole-4-carboxylic acid ethyl ester;
Q 2-[5-tert-Butyl-2-methoxy-3-(3-{4-[2-(pyrrolidine-l-carbonyl)-
pyridin-4-yloxy]-naphthalen-l-yl}-ureido)-pheaylamino]-
thiazole-4-carboxylic acid ethyl ester;
2-(5-tert-Butyl-2-methoxy-3- {3-[4-(2-methylaminomethyl-
X^T Pyridin-4-yloxy)-naphthalen-l-yl]-ureido}-pheaylamino)-
thiazole-4-carboxylic acid ethyl ester;
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2-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-methyIcarbamoyl-pyridin-
4-yloxy)-naphthalen- 1 -yl]-ureido} -phenylamino)-thiazole-4-
carboxylic acid ethyl ester;
2-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-mediylamirio-pyridin-4-
yloxy)-naph1halen-l-yl]-iireido}-phenylamino)-thiazole-4--
carboxylic acid ethyl ester;
o 1 - {5-tert-Butyl-2-methoxy-3-[4-(pyrrolidine- 1 -carbonyl)-thiazol-
"iQ, 2-ylairdno]-phenyl}-3-[4-(pyridin-4-yloxy)-naphthalen-l-yl]-urea;
Y ^^0^-^ l-[5-tert-Butyl-2-me1hoxy-3-(4-pyrrolidin-l-ylmethyl-thiazol-2-
j^AtI ylamino)-phenyl]-3-[4-(pyridin-4-yloxy)-naphthalen-l-yl]-urea;
2-(5-tert-Butyl-2-me1hoxy-3-{3-[4-(pyririiidin-4-yloxy)-
naphthalen-l-yl]-ureido}-phenylaniino)-thiazole-4-carboxylic
acid ethyl ester;
2-(3 - {3- [4-(2-Amino-pyrimidin-4-yloxy)-naphthalen- 1 -yl]-
ureido}-5-tert-bai1yl-2-methoxy-phenylaiiiino)-tbiazole-4-
carboxylic acid ethyl ester;
2-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-methylamino-pyrimidin-4-
yloxy)-naph&alen-l-yl]-ureido}-phenylainino)-thiazole-4-
carboxylic acid ethyl ester;
2-[5-tert-Buryl-3-(3-{4-[2-(cyclopropylmelhyl-amino)-pyrimidin-
4-yloxy]-naphthalen- 1 -yl} -ureido)-2-methoxy-phenylamino]-
tbiazole-4-carboxylic acid ethyl ester;
2-(5-tert-Butyl-2-methoxy-3-{3-[4-(pyrimidin-4-yloxy)-
naphthalen- 1 -yl]-ureido} -phenylamino)-thiazole-4-carboxylic
acid (2-dimetbylamino-ethyl)-methyl-amide;
1 - {5-tert-Butyl-2-methoxy-3-[4-(pyrrohdine- 1 -carbonyl)-thiazol-
2-ylamino]-phenyl} -3-[4-(pyriiiiidin-4-yloxy)-naphthalen- 1 -yl] -
urea;
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l-[5-tert-Butyl-2-methoxy-3-(4-pyrroUdin-l-ylmethyl-thiazol-2-
ylaiiiino)-phenyl]-3-[4-(pyriiiiidin-4-yloxy)-naphthalen- 1 -yl]-
urea;
o
l-[5-tert-Butyl-2-methoxy-3-(4-pyrrolidin-l-ylmethyl-thiazol-2-
ylamino)-phenyl]-3-[4-(2-isopropylamino-pyrimidiu-4-yloxy)-
naphthalen-l-yl]-urea;
1- {5-tert-Butyl-2-methoxy-3-[4-(pyrrolidine-l-carbonyl)-thiazol-
2- ylamino]-phenyl} -3- {4-[2-(cyclopropyImethyl-amino)-6-
methyl-pyrimidin-4-yloxy]-naphthalen-l-yl}-urea;
1 -[5-tert-Butyl-2-methoxy-3-(4-pyrrolidin- 1 -ylmethyl-thiazol-2-
ylamino)-phenyl]-3-{4-[2<cyclopropylmethyl-amino)-6-methyl-
pyrimidin-4-yloxy]-naphthalen- 1 -yl} -urea;
l-[5-tert-Butyl-3-(3-dimethylamino-pynrolidin-l-ylinethyl)-2-
methoxy-phenyl]-3-[4-(pyridin-4-yloxy)-naphthalen-l-yl]-urea;
i ^v^o^^ l-[5-tert-Butyl-3-(3-dimethylaininomethyl)-2-methoxy-plienyl]-3-
i^jOk B A R XXT^ [4-(pyridin-4-yloxy)-naphthalen-l-yl]-urea;
1 -[5-tert-Butyl-3 -(3-dimethylamino-pyirolidin- 1 -ylmethyl)-2-
methoxy-phenyl]-3-[4-(2-dimethylaminomethyl-pyridin-4-yloxy)-
naphthalen- 1 -y 1] -urea;
l-[5-tert-Butyl-3-(3-dimethylamino-pyrrolidin-l-y]methyl)-2-
methoxy-phenyl]-3-[4-(pyriinidin-4-yloxy)-naphthalen-l-yl]-urea;
l-[4-(2-Amino-pyrinudin-4-yloxy)-naph1lialen-l-yl]-3-[5-tert-
butyl-3 -(3 -dimethy lamino-pyrrolidin- 1 -ylmethyl)-2-methoxy-
phenyl]-urea;
,1.
s ^ l-[4-(2-Ammo-6-methyl-pyriimdm
[5-tert-butyl-3-(3-dimethylamino-pyrroUdin-l-ylmethyl)-2^
methoxy-phenyl]-urea;
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WO 02/092576 PCTAJS02/14733
l-(5-tert-Butyl-3-dime1hylaminomethyl-2-methoxy-phenyl)-3-{4-
[2-(cycIopropylmethyl-amino)-pyriinidin-4-yloxy]-naphth^^
yl}-urea;
l-(5-tert-Butyl-3-dimethylaminomethyl-2-methoxy-phenyl)-3-{4-
[2-(cyclopropylmethyl-amino)-6-methyl-pyrimidin-4-yloxy]-
naphthalen-l-yl}-urea;
f> N-[5-tert-Butyl-2-methoxy-3-(3-{4-[2-(2-methoxy-phenyl)-
f fY°TVT Pyri^din-4-yloxy]-naphthalen-l-yl}-ureido)-phenyl]-
>/^ s methaaesulfonamide;
" 4-{4^[3-(5-tert-Butyl-3-metlianesulfonylainino-2-methoxy-
o phenyl)-ureido] -naphthalen- 1 -yloxy} -pyrimidine-2-carboxylic
acid methyl ester;
iO* l-[4-(2-Acetyl-pyrimidm-4-yloxy)-naphthalen-l-yl]-3-(5-tert-
1 N XXXX° butyl-2-methoxy-phenyl) -urea:
N-(3- {3 -[4-(2-Atetyl-pyrimidiii-4-yloxy)-naphthalen- 1 -yl]-
°YV !>0 ureido} -5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide;
o J l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(l-pyrroUdin-l-yl-
v ||Vri^^ ethyl)-pyrimidin-4-yloxy]-napb.thalen-l-yl}-wea;
. N-[5-tert-Butyl-2-methoxy-3-(3- {4-[2-(l -pyrrolidin- 1 -yl-ethyl)-
VVSq pyrimidin-4-yloxy]-naphthalen-l-yl}-ureido)-phenyl]-
methanesulfonamide;
. l-(2-methoxy-5-trimethylsilanyl-phenyl)-3-{4-[2-
jOC°X!!T (cyclopropylmethyl-anmo)-pyrimidm^-yloxy]-naphthalen-l-yl^
or the pharmaceutically acceptable derivatives thereof.
In all the compounds disclosed above, in the event the nomenclature is in conflict with
the structure, it shall be understood that the compound is defined by the structure.
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Any compounds of this invention containing one or more asymmetric carbon atoms may
occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures
and individual diastereomers. All such isomeric forms of these compounds are expressly
included in the present invention. Each stereogenic carbon may be in the R or S
5 configuration, or a combination of configurations.
Some of the compounds of the invention can exist in more than one tautomeric form.
The invention includes all such tautomers. It shall also be understood that the invention
includes all homologs, analogs, optical and positional isomers thereof.
10
All terms as used herein in this specification, unless otherwise stated, shall be understood
in their ordinary meaning as known in the art.
Any of the aromatic ring systems, carbocyclic or heterocyclic, shall be understood to
15 include the non-aromatic ring systems which may be mono- or polyunsaturated, and the
positional isomers or analogs thereof.
Any of the compounds described hereinabove possessing "nitrogen" and "sulfur'' shall
include any oxidized form of nitrogen and sulfur and the quaternized form of any basic
20 nitrogen.
The compounds of the invention are only those which are contemplated to be 'chemically
stable' as will be appreciated by those skilled in the art. For example, a compound which
would have a 'dangling valency', or a 'carbanion' are not compounds contemplated by
25 the invention.
The invention includes pharmaceutically acceptable derivatives of the novel compounds
disclosed herein. A "pharmaceutically acceptable derivative" refers to any
pharmaceutically acceptable salt or ester of a compound of this invention, or any other
30 compound which, upon administration to a patient, is capable of providing (directly or
indirectly) a compound of this invention, a pharmacologically active metabolite or
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pharmacologically active residue thereof. A pharmacologically active metabolite shall be
understood to mean any of the novel compounds disclosed herein capable of being
metabolized en2ymatically or chemically. This includes, for example, hydroxylated or
oxidized derivative compounds.
Pharmaceutically acceptable salts of the compounds of this invention include those
derived from pharmaceutically acceptable inorganic and organic acids and bases.
Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric,
fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric,
tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric
and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves
pharmaceutically acceptable, may be employed in the preparation of salts useful as
intermediates in obtaining the compounds of this invention and their pharmaceutically
acceptable acid addition salts. Salts derived from appropriate bases include alkali metal
(e.g., sodium), alkaline earth metal {e.g., magnesium), ammonium and N-^-^
alkyl) 4 + salts.
In addition, the compounds of this invention include prodrugs of compounds of the the
novel compounds disclosed herein. Prodrugs include those compounds that, upon simple
chemical transformation, are modified to produce compounds of the invention. Simple
chemical transformations include hydrolysis, oxidation and reduction. Specifically, when
a prodrug of this invention is administered to a patient, the prodrug may be transformed
into a novel compound of the invention, thereby imparting the desired pharmacological
effect.
METHODS OF TISP.
In accordance with the invention, there are provided methods of using the compounds of
the invention. The compounds of the invention effectively block inflammatory cytokine
production from cells. The inhibition of cytokine production is an attractive means for
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preventing and treating a variety of cytokine mediated diseases or conditions associated
with excess cytokine production, e.g., diseases and pathological conditions involving
inflammation. Thus, the compounds of the invention are useful for the treatment of such
conditions. These encompass diseases including, but not limited to, rheumatoid arthritis,
osteoarthritis, traumatic arthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn's
disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus
erythematosus, glomerulonephritis, reperfusion injury, sepsis, bone resorption diseases
including osteoporosis, chronic obstructive pulmonary disease, congestive heart failure,
Alzheimer's disease, atherosclerosis, toxic shock syndrome, asthma, contact dermatitis,
percutaneous transluminal coronary angioplasty (PTCA) and insulin-dependent diabetes
mellitus.
In addition, the compounds of the invention being inhibitors of cytokine production are
expected to block inducible cyclooxygenase (COX-2) expression. COX-2 expression has
been shown to be increased by cytokines and it is believed to be the isoform of
cyclooxygenase responsible for inflammation (M.K. O'Banion et al, Proc. Natl. Acad.
Sci. U.S.A, 1992, 89, 4888.) Accordingly, the present novel compounds would be
expected to exhibit efficacy against those disorders currently treated with COX inhibitors
such as the familiar NSAIDs. These disorders include acute and chronic pain as well as
symptoms of inflammation and cardiovascular disease.
As discussed in the Background of the Invention, IL-8 plays a role in the influx of
neutrophils into sites of inflammation or injury. Therefore, in a yet further aspect of the
invention, the compounds of the invention may be useful in the treatment of diseases
mediated predominantly by neutrophils such as stroke and myocardial infarction, alone or
following thrombolytic therapy, thermal injury, adult respiratory distress syndrome
(ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis,
dermatoses with acute inflammatory components, acute purulent meningitis or other
central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion
associated syndromes, and necrotizing entrerocolitis.
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For therapeutic use, the compounds of the invention may be administered in any
conventional dosage form in any conventional manner. Routes of administration include,
but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by
infusion, sublingually, transdermally, orally, topically or by inhalation. The preferred
5 modes of administration are oral and intravenous.
The compounds of this invention may be administered alone or in combination with
adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutic
compositions containing them in certain embodiments, provide increased dissolution or
10 dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including
other active ingredients. Advantageously, such combination therapies utilize lower
dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side
effects incurred when those agents are used as monotherapies. Compounds of the
invention may be physically combined with the conventional therapeutics or other
15 adjuvants into a single pharmaceutical composition. Advantageously, the compounds
may then be administered together in a single dosage form. In some embodiments, the
pharmaceutical compositions comprising such combinations of compounds contain at
least about 5%, but more preferably at least about 20%, of a compound of the invention
(w/w) or a combination thereof. The optimum percentage (w/w) of a compound of the
20 invention may vary and is within the purview of those skilled in the art. Alternatively,
the compounds may be administered separately (either serially or in parallel). Separate
dosing allows for greater flexibility in the dosing regime.
As mentioned above, dosage forms of the compounds of this invention include
25 pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the
art. These carriers and adjuvants include, for example, ion exchangers, alumina,
aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes
and cellulose-based substances. Preferred dosage forms include, tablet, capsule, caplet,
liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule,
30 suppository and transdermal patch. Methods for preparing such dosage forms are known
(see, for example, H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and
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Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and
requirements are well-recognized in the art and may be selected by those of ordinary skill
in the art from available methods and techniques suitable for a particular patient. In some
embodiments, dosage levels range from about 1-1000 mg/dose for a 70 kg patient.
Although one dose per day may be sufficient, up to 5 doses per day may be given. For
oral doses, up to 2000 mg/day may be required. As the skilled artisan will appreciate,
lower or higher doses may be required depending on particular factors. For instance,
specific dosage and treatment regimens will depend on factors such as the patient's
general health profile, the severity and course of the patient's disorder or disposition
thereto, and the judgment of the treating physician.
In order that this invention be more fully understood, the following examples are set
forth. These examples are for the purpose of illustrating preferred embodiments of this
invention, and are not to be construed as limiting the scope of the invention in any way.
The examples which follow are illustrative and, as recognized by one skilled in the art,
particular reagents or conditions could be modified as needed for individual compounds
without undue experimentation. Starting materials used in the scheme below are either
commercially available or easily prepared from commercially available materials by
those skilled in the art.
GENERAL SYNTHETIC METHODS
The invention additionally provides for methods of making the compounds of the the
invention. The compounds of the invention and intermediates used in their preparation
may be prepared by the general methods and examples presented below, and methods
known to those of ordinary skill in the art. Further reference in this regard may be made
to the general methods and examples found in US patent, nos. 6,319,921 and 6,358,945,
US application nos. 09/714,539, 09/611,109, 09/698,442, 09/834,797 and 09/902,085,
and US provisional application no. 60/283,642. Each of the aforementioned are
incorporated herein by reference in their entirety. In all schemes "L" in the formulas
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shown below shall be defined as moieties on the left side of the urea bond, "R" shall be
understood to mean all possible moieties on the right side of the urea bond. For example,
the left side 'L' and the right side 'R' of the compound
5 respectively.
The compounds of the invention may be prepared by Method A, B, C or D as illustrated
in Scheme I, preferably Method C.
Scheme I
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Method A
NH 2
lla
OCN-R
III
O
H H
(or a precursor)
Method B
lla
1 . phosgene
2. H,N-R
IV
o
H H
(or a precursor)
Method C
NH 2
lla
CIC0 2 Ph
U l 0 .Ph
H
V
IV
(or a precursor)
Method D
'COOH
lib
1 . ethyl chloroformate
2. sodium azide L>«
3. heat
NCO
Va
IV
O
H H
(or a precursor)
In Method A, a mixture of an arylamine of formula Ha and an arylisocyanate of formula
III is dissolved in a non-protic, anhydrous solvent such as THF, ether, toluene, dioxane or
ethyl acetate. The preferred solvent is THF. The mixture is stirred at between 0 - 45° C,
preferably at 25° C, for 2-24 h, and the volatiles are removed. Purification of the residue
can be accomplished by recrystallization from an appropriate solvent such as ethyl
acetate/hexanes, ethyl acetate/methanol, THF/petroleum ether or ethanol/water or by
silica gel chromatography, using for example, hexanes and ethyl acetate as eiuents,
providing the product compound or precursors thereof.
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In Method B, an arylamine of formula Ha is dissolved in a halogenated solvent, such as
methylene chloride, chloroform or dichloroethane. The preferred solvent is methylene
chloride. The mixture is diluted with aqueous alkali, such as sodium bicarbonate or
potassium carbonate, cooled in an ice bath and phosgene is added. The mixture is
5 vigorously stirred for 5-30 rnin, with 10 min being preferable. The organic layer is
dried, with agents such as MgS0 4 or Na 2 SC>4, and the volatiles removed to provide the
corresponding isocyanate. The isocyanate and arylamine IV are mixed in a non-protic,
anhydrous solvent such as THF, ether, toluene, dioxane, methylene chloride or ethyl
acetate. The preferred solvent is THF. The mixture is stirred at between 0 - 45° C,
10 preferably at 25° C, for 2 - 24 h, and the volatiles are removed. Purification of the residue
by recrystallization or by silica gel chromatography, as above, provides the product
compound or precursors thereof.
In Method C, an arylamine of formula Ha is dissolved in a suitable halogenated solvent
such as methylene chloride, chloroform or dichloroethane. The preferred solvent is
15 methylene chloride. A suitable base such as triethylamine may be added, followed by an
alkyl or aryl chloroformate, such as f-butyl chloroformate or phenyl chlorofonnate
(shown). The mixture is stirred at between 0 - 85° C, preferably at reflux temperature, for
2 - 24 h, and the volatiles are removed providing carbamate V. The carbamate and
aiylamine IV are mixed in a non-protic, anhydrous solvent such as THF, ether, toluene,
20 dioxane, methylene chloride or ethyl acetate. The preferred solvent is THF. The mixture
is stirred at between 0 - 1 10 °C, preferably at reflux temperature, for 2 - 24 h, and the
volatiles are removed. Purification of the residue as above provides the product
compound or precursors thereof.
25 In Method D, an aromatic carboxylic acid (lib) is dissolved in a non-protic solvent, such
as THF or diethyl ether, and an inorganic base, such as triethyl amine is added and the
mixture is cooled to -30-0°C, with the preferred temperature being -10°C. An alkyl
chloroformate, such as ethyl chloroformate, is added dropwise and the resulting mixture
stirred at below room temperature, such as 0°C for 1-3 hours. A solution of sodium azide
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in water is added and the mixtiure stirred between 1-3 hours, diluted with toluene and the
organic layer dried and reduced in volume. This mixture is heated at reflux for 1-4 hours,
cooled to room temperature to give isocyanate (Va) which can be reacted with amine
(TV) to give the product compound or precursors thereof.
EXPERIMENTAL SECTION
Amine intermediates of formula Ha are either commercially available or may be prepared
by methods known to those skilled in the art. Examples 1-4 are representative of
procedures for preparing aryl amine or aryl isocyanate derivatives that may be used in
Methods A-D. It will be apparent to those skilled in the art that other desired
intermediates could be made by these methods by using appropriately substituted starting
materials and intermediates.
Example 1: Synthesis of l-(5-tert-butyl-2-methoxy-phenyl)-3-
[4-(2-cyano-pyrimidin-4-yloxy)-naphthalen-l-yl]-urea
To a 0 °C solution of trimethyl amine (20% solution in water, 3.8 mmol) in 2 mL of
dimethylformamide was added 4-(2-cMoro-pyrinudm-4-yloxy)-naphthalen-l-ylamine
(270 mg, 1 mmol). The deep tan solution was warmed to room temperature for 3 h,
during which the initially light suspension became a brown suspension. After this time,
tetraethylammonium cyanide (156 mg, 1 mmol) was added all at once to provide a deep
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amber solution. After 1 h, the reaction was quenched with water, extracted with EtOAc
and dried over magnesium sulfate. Column chromatography (10-60% EtOAc-hexanes)
provided 142 mg (54%) of 4-(4-ammo-naphmalen-l-yloxy)-pyrirm
To a 0 °C biphasic solution of the above nitrile (47 mg, 0.18 mmol) was added 0.3 mL
(2.6 mmol) of phosgene. The solution was stirred for 15 min at 0 °C, then warmed to
room temperature for 1 h. After this time, the reaction was extracted, dried over MgS0 4
and concentrated in vacuo. The resulting orange solid was added to a solution of tert-
butyl anisidine (75 mg, 0.35 mmol). The reaction was stirred overnight , concentrated in
vacuo, and triturated with 3:1 hexanes: EtOAc to provide 55 mg (69%) of the title
compound as an off-white solid.
Example 2: Synthesis of N-(5-tert-butyI-2-methoxy-3-{3-[4-(tetrahydro-pyran-4-
yloxy)-naphthalen-l-yl]-ureido}-phenyl)-methanesulfonamide
Triphenylphosphine (2.8 g, 10.8 mmol) was dissolved in THF (5 mL) and cooled to 0 °C.
To this colorless solution diethylazodicarboxylate (1.9 grams, 10.8 mmol)was added
drop wise to afford an orange solution. After 15 min at 0 °C, a copious precipitate had
formed. 4-Hydroxy-naphthalen-l-yl-carbamic acid tert-butyl ester (934 mg, 3.6 mmol)
and tetrahydro-4if-pyran-4-ol (552 mg, 5.4 mmol) were then added in one portion as a
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solution in 2 mL of THF. The puiple suspension was stirred at 0 °C for one h then at
room temperature for 48 h. The solvent was then evaporated and chromatographed on
silica gel (40% EtOAc-hexanes) to provide 680 mg (55%) of [4-(tetrahydro-pyran-4-
yloxy)-naphthalen- l-yl]-carbamic acid tert-butyl ester as a purple solid.
5
The above tert-butyl ester (680 mg, 1.98 mmol) was dissolved in CH 2 C1 2 (5 mL) and to
the purple solution was added trifluoroacetic acid (1. 14 g, 10 mmol) and the reaction was
stirred overnight at room temperature. The reaction was then diluted with CH 2 C1 2 (50
mL) and washed with 50% saturated aqueous NaHCC>3 (50 mL). The organic portion
10 was then washed with water, brine, dried over Na 2 SC>4, and concentrated in vacuo
provide 460 mg (95%) of 4-(tetxahydro-pyran-4-yloxy)-naphmalen-l-ylarnine as a purple
solid.
The title compound was prepared from the above amine and N-(3-amino-5-tert-butyl-2-
15 methoxyphenyl)methanesulfonamide by the procedure described for l-(5-tert-butyl-2-
methoxy-phenyl)-3-[4-(2-cyano-pyrirmdin-4-yloxy)-naphthalen-l-yl]-urea (Example 1).
Example 3: Synthesis of 4-{4-[3-(5-tert-butyl-2-methoxy-phenyl)-ureido]-
20 naphthalen-l-yloxy}-pyrirnidine-2-carboxyIic acid methyl ester
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To a solution of [4-(2-iodo-pyrimidin^-yloxy)-naphthalen-l-yl]-carbamic acid tert-butyl
5 ester (1 00 mg, 0.44 mmol) in 2 mL of DMF, was added, 0.5 mL MeOH, 0. 12 mL of Et 3 N
(0.9 mmol), Pd(OAc) 2 (10 mg, 0.04 mmol), and DPPF (44 mg, 0.4 mmol). The reaction
was heated under a CO balloon at 60 °C for 5 h. The reaction was then diluted with
EtOAc, concentrated in vacuo on silica gel and chromatographed directly with 10-80%
EtOAc-hexanes to provide 26 mg (14%) of 4-(4-tert-butoxycarbonylamino-naphthalen-l-
s
10 yloxy)-pyrimidine-2-carboxylic acid methyl ester as a brown solid.
To a solution of the above methyl ester (176 mg, 0.47 mmol) was added 5 mL of TFA.
After 2 h, the reaction was concentrated in vacuo. The brown solid was suspended in
toluene and concentrated in vacuo two more times. Ether trituration provided 94 mg
1 5 (74%) of 4-(4-amino-naphthalen- 1 -yloxy)-pyrimidine-2-carboxylic acid methyl ester as a
brown solid, which is used without further purification.
The title compound was prepared from the above amine and 5-tert-butyl-2-
memoxyaniline by the procedure described for l-(5-tert-butyl-2-methoxy-phenyl)-3-[4-
(2-cyano-pyrimidin-4-yloxy)-naphlhalen-l-yl]-urea (Example 1).
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Example 4: Synthesis of l-(2-methoxy-5-trimethylsUanyl-phenyl)-3-[4-(6-morpholin-
4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-urea
To a - 30 °C solution of 4-methoxyplienyl trimethyl silane prepared from 4-bromoanisole
via the procedure of Ellman et al ( J. Org. Chem. 1997, 62, 6102) (1.5 g, 8.3 mmol) was
10 added NO2BF4 (1 . 1 g, 8.4 mmol) in CH 3 CN. The resulting deep brown solution was
stirred for 20 min, then water was added and the reaction was extracted with EtOAc,
dried over MgS0 4 and concentrated in vacuo. The crude material was chromatographed
on silica gel (25% EtOAc-hexanes) to provide 760 mg (40%) of (4-methoxy-3-nitro-
phenyl)-trimethyl-silane as a gold oil.
15
The above trimethyl-silane (760 mg, 3.4 mmol) was dissolved in 25 mL of EtOH. To
this was added 10% Pd/C (128 mg). The reaction was stirred for 12 h under a 1 atm
• balloon of hydrogen gas. The reaction was then filtered through diatomaceous earth and
concentrated in vacuo to provide 400 mg (60%) of 2-memoxy-5-trimethylsilanyl-
20 phenylamine as an amber oil which was used without further purification.
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The title compound was prepared from the above amine and 4-[5-(4-
ammonaphmyl)pyridm-2-ylmethyl]morpholine by the procedure described for l-(5-tert-
butyl-2-memoxy-phenyl)-3-[4-(2-cyano-pyrimidm^-yloxy)-naphthalen-l-yl]-urea
5 (Example 1).
10
Example 5: Synthesis of l-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(2-methyl-
pyrimidin-4-yloxy)-naphthalen-l-yl]-urea
dppf, dmf
HO. ,OH
l-(5-tert-Butyl-2-mefooxy-phenyl)-3-[4-(2-c^^
urea (50 mg, 0.1 mmol) was dissolved in 0.4 mL of DMF. To this was added
15 PdCl 2 (PPh 3 ) 2 (10 mol%), o-methoxyboronic acid (32 mg, 0.2 mmol) in 2 mL of
DME/H 2 0/EtOH (7:3:2) and 0.53 mL of Na 2 C0 3 (2M). The reaction was heated in a
Smith synthesizer microwave for 3 min at 160 °C. The product was concentrated on
silica and purified (15-30% EtOAc-hexanes) to provide 13 mg (23%) of the title
compound as an off-white foam.
20
Example 6: Synthesis of 2-(5-tert-butyl-2-methoxy-3-{3-[4-(pyridin-4-yloxy)-
naphthalen-l-yl]-ureido}-phenylaniino)-thiazole-4-carboxylic acid ethyl ester
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To a solution of N-(5-tert-butyl-2-methoxy-3-nitrophenyl) thiourea (l.Og, 3.55 mmol) in
EtOH (20 mL) was added bromoethylpyruvate (727 mg, 3.73 mmol). This solution was
5 heated to reflux for 12h. The TLC showed consumption of all starting thiourea and
formation of one new product spot. The solvent was removed under vacuum and the
resulting solid triturated by a mixture of hexane/EtOAc (2: 1) to get the desired thiazole
product as a yellow solid (1.2 g, 86% yield).
10 To a solution of the above thiazole ( 1 g, 2.66 mmol) in a mixture of THF/EtOAc ( 1 : 1 , 60
mL) palladium on carbon (10%, 200 mg) was added in one portion. The black yellow
suspension was subjected to hydrogen pressure (50 psi) for 16 h. The catalyst was
removed by filtration through diatomaceous earth, and the resulting solution was
concentrated to give the desired aniline intermediate as a thick, brown oil.
15
To a solution of the above aniline (100 mg, 0.29mmol) in dichloromethane (2 mL) was
added a preformed solution of 4-(pyridin-4-yloxy)-naphthalen-l-yl isocynate (250 mg,
0.86 mmol) in dichloromethane 2mL. This solution was stirred at room temperature for
12 h. The solvent was removed by rotary evaporation and the resulting oil purified on a
20 flash silica gel column eluting with a dichloromethane-MeOH mixture (95:5) to provide
the title compound as light brown foam (50 mg, 29% yield).
Example 7: Synthesis of l-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(2-isopropyl-6-
methyl-pyrimidin-4-yloxy)-naphthalen-l-yl]-urea
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Boron trifluoride etherate (4.0 mL, 31.1 mmol, 1.5 equiv.) was cooled on an ice bath
under inert atmosphere in a dry round bottom flask. 4-Arnino-l-nitronaphthalene ( 3.9 g,
20.7 mmol, lequiv.) dissolved in 100 mL anhydrous DME was added slowly, over 10
5 min. After stirring 15 min, tert-butyl nitrite ( 3.0 mL, 24.8 mmol, 1.2 equiv.) was added
dropwise via syringe. The ice bath was removed and the mixture was stirred at room
temperature for 1.5 h. A precipitate of golden green color had formed. The mixture was
then re-cooled to 0 °C and the precipitated 4-nitro-naphthalene diazonium
tetrafluoroborate salt 5.1 g (17.7 mmol or 86 %) was collected via vacuum filtration
10 through a Buchner funnel.
The diazonium salt from above (408 mg, 1.42 mmol, 1 equiv.) was mixed with silica gel
(63-200 micron, 2500 mg) and rendered homogeneous by light mixing in a mortar. This
mixture was placed in a round bottom flask equipped with a mechanical stirrer and a
15 condenser, and heated to 150-170 °C for 0.5 h. The mixture turned dark. The solid
mixture was allowed to cool back to room temperature, placed on top of a short plug of
silica gel, the transfer being aided by some hexanes solvent. The pure 4-fhioro-l-
nitronaphthalene product was eluted with 10% EtOAc in hexanes. After removal of the
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solvents in vacuo 190 mg of product (0.99 mmol, 70% yield) was collected as a yellow-
orange solid.
2-Isopropyl-6-memyl-4-pyrimidinol ( 264 mg, 1.74 mmol, 1.1 equiv.) was dissolved in
5 2.5 mL anhydrous DMSO. Sodium tert-butoxide ( 159 mg, 1.66 mmol, 1.05 equiv.) was
added in one portion and the mixture was left stirring for 15 min at room temperature.
Solid 4-fluoro-l-nitro-naphthalene was then added in one portion and the mixture was
gently heated to 60 °C while stirring for 4 h. A color change from orange to green was
noted. Saturated aqueous sodium bicarbonate solution was then added and the product
10 extracted 3 times with EtOAc. The combined organic extracts were washed once with
water and with brine, dried (Na 2 S0 4 ) and fdtered. The volatiles were removed in vacuo to
afford a waxy orange solid. Crude yield was 459 mg (1.42 mmol or 90%). The material
was used without purification for the next step.
15 The crude nitronaphmyl-pyrirnidinyl ether from above (459 mg, 1 .42 mmol, 1 equiv.)
was taken up in 35 mL EtOAc and 35 mL EtOH. Ammonium formate was added (537
mg, 8.52 mmol, 6 equiv.) as well as 400 mg of 10% palladium-on-carbon. The reaction
mixture was heated to a gentle reflux for one h, cooled back to room temperature, filtered
through diatomaceous earth and the volatiles were removed in vacuo. The crude product
20 was purified by chromatography on Si0 2 , eluting with 20-40% EtOAc in hexanes. The
desired arnmonaphmyl-pyrimidinyl ether was isolated as a yellow foam (176 mg, 0.6
mmol, 42 % for 2 steps).
5-tert-Butyl-ortho-anisidine ( 107 mg, 0.60 mmol, 1 equiv.) was dissolved in 25 mL
25 dichloromethane and 20 mL saturated aqueous sodium bicarbonate solution was added.
The mixture was cooled to 0 °C. Without stirring, phosgene (2.0 M in toluene, 1.05 mL,
2. 1 mmol, 3.5 equiv.) was added in one portion to the organic layer via syringe. After 1 5
min the layers were separated and the aqueous phase was extracted with one portion of
dichloromethane. The combined organics were dried (Na 2 S0 4 ), filtered and the majority
30 of the solvent was removed in vacuo. To this isocyanate residue was immediately added a
solution of the naphtoylammo-pyrimidinyl ether from above (88 mg, 0.3 mmol, 0.5
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equiv.) in 2.5 mL anhydrous THF. The mixture was left stirring at room temperature
overnight, then MeOH was added and the solvents removed in vacuo. A purple foam was
obtained, which was purified by column chromatography on Si0 2 , eluting with 0-10 %
MeOH in dichloromethane. Recrystallization from acetonitrile/water afforded 76 mg of
5 the title compound as a white solid (0.15 mmol, 50 % yield).
Example 8: Synthesis of N-(3-{3-[4-(2-isopropyl-6-methyl-pyrimidin-4-yloxy)-
naphthalen-l-yl]-ureido}-5-tert-butyl-2-methoxy-phenyl)-methanesulfonaniide
The intermediate naphmylamino-pyrimidinyl ether from Example 7 (104 mg, 0.36 mmol,
1 equiv.) was dissolved in 20 mL dichloromethane and 20 mL saturated aqueous sodium
bicarbonate solution was added. The mixture was cooled to 0 °C. Without stirring,
phosgene (2.0 M in toluene, 0.62 mL, 1.24 mmol, 3.5 equiv.) was added in one portion to
15 the organic layer via syringe. After 15 min the layers were separated and the aqueous
phase was extracted with one portion of dichloromethane. The combined organics were
dried (NazSO*), filtered and the majority of the solvent was removed in vacuo. To this
isocyanate residue was immediately added a solution of N-(3-ammo-5-tert-butyl-2-
methoxy-phenyl)-methanesulfonamide (97 mg, 0.36 mmol, 1 equiv.) in 2.5 mL
20 anhydrous THF. The mixture was left stirring at room temperature overnight, then MeOH
was added and the solvents removed in vacuo. A purple foam was obtained, which was
purified by column chromatography on Si02, eluting with 0-10 % MeOH in
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dichloromethane. Finally recrystallization from acetonitrile/water afforded 45 mg of the
tide compound as a white solid (0.08 mmol, 21 % yield).
Example 9: Synthesis of l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{2-[(pyridin-2-
ylmethyl)-amino]-pyrimidin-4-yloxy}-naphthalen-l-yl)-urea
4-Aminonaphthol hydrochloride (4.40 g, 22.5 mmol, 1 equiv.) was dissolved in 30 mL
anhydrous DMSO at room temperature and was treated with potassium tert-butoxide
(5.05 g, 45.0 mmol, 2 equiv.). After 30 min 2,4-dicWoropyrimidine (3.34 g, 22.5 mmol, 1
equiv.) in 12 mL anh. DMSO was added via cannula. Once the addition was complete,
the mixture was heated to 60 °C for 3 h, then allowed to cool. Water (200 mL) was added
and the product extracted with EtOAc (3 x 50 mL). Combined extracts were washed
twice with water and once with brine, then dried (Na 2 S0 4 ). A golden brown foam (6.60
g) was obtained after filtration and removal of solvents in vacuo. The crude product was
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purified by column chromatography on Si0 2 using 35% EtOAc in hexanes as eluent. The
purified product was isolated as an orange solid (4.68 g, 17.2 mmol, 76% yield).
The cuchloropyrimidine-naphthylamine ether from above (1.04 g, 3.83 mmol, 1 equiv.)
5 was dissolved in 100 mL dichloromethane and 75 mL of a saturated aqueous solution of
sodium bicarbonate was added. The mixture was cooled to 0 °C. Without stirring,
phosgene (~2 M in toluene, 6.7 mL, 13.4 mmol, 3.5 equiv.) was added via syringe to the
organic layer in one portion. Stirring was resumed for 20 min, then the layers were
separated. The organic layer was dried (Na 2 S0 4 ), filtered, and the solvent was removed
10 in vacuo, leaving ~ 5 mL of toluene. To this residue was immediately added tert-butyl-
ortho-anisidine (687 mg, 3.83 mmol, 1 equiv.) in 18 mL anh. THF at room temperature,
and the mixture was left stirring for 4 h. The solvents were then removed in vacuo
leaving a yellow solid , which was triturated to a white powder in hot EtOAc. The
intermediate chloropyrimidine-urea was thus isolated (1.23 g, 2.58 mmol, 67 % yield).
15
The final substitutions of the chloropyrimidine from above, to afford a number of
different ammopyrimidines, were carried out in parallel, and are exemplified here with 2-
arninomethylpyridine.
20 The cMoropyrimidine-urea (70 mg, 0.147 mmol, 1 equiv.) was dissolved in 1 mL
anhydrous THF. Triethylamine (21 uL, 0.147 mmol, 1 equiv.) was added, followed by a 1
M solution of 2-ammomemylpyridine in THF (0.15 mL, 0.15 mmol, 1 equiv.). The
mixture was sealed in a pressure tube and heated to 75 °C for 96 h. Water was added and
the product extracted with EtOAc and purified by column chromatography on SiC>2 using
25 3 % MeOH in dichloromethane. An orange foam was obtained and the product was
further purified by recrystallization from hot CH3CN to provide the title compound (29
mg), mp 148-150 °C.
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ASSESSMENT OF BIOLOGICAL PROPERTIES
Inhibition of TNF Production in THP Cells
The inhibition of cytokine production can be observed by measuring inhibition of TNFa
in lipopolysaccharide stimulated THP cells (for example, see W. Prichett et al, 1995, J.
Inflammation, 45, 97). All cells and reagents were diluted in RPMI 1640 with phenol red
and L-glutamine, supplemented with additional L-glutamine (total: 4 mM), penicillin and
streptomycin (50 units/ml each) and fetal bovine serum (FBS, 3%) (GIBCO, all cone,
final). Assay was performed under sterile conditions; only test compound preparation was
nonsterile. Initial stock solutions were made in DMSO followed by dilution into RPMI
1640 2-fold higher than the desired final assay concentration. Confluent THP.l cells
(2x1 0 6 cells/mL, final cone; American Type Culture Company, Rockville, MD) were
added to 96 well polypropylene round bottomed culture plates (Costar 3790; sterile)
containing 125 uL test compound (2 fold concentrated) or DMSO vehicle (controls,
blanks). DMSO concentration did not exceed 0.2% final. Cell mixture was allowed to
preincubate for 30 min, 37°C, 5% CO2 prior to stimulation with lipopolysaccharide (LPS;
1 ng/mL final; Siga L-2630, from E.coli serotype 01 1 1.B4; stored as 1 mg/mL stock in
endotoxin screened distilled H 2 0 at -80°C). Blanks (unstimulated) received H 2 0 vehicle;
final incubation volume was 250 jal. Overnight incubation (18-24 hr) proceeded as
described above. Assay was terminated by centrifuging plates 5 min, room temperature,
1600 rpm (400 x g); supematants were transferred to clean 96 well plates and stored -
80°C until analyzed for human TNFa by a commercially available ELISA kit (Biosource
#KHC3015, Camarillo, CA). Data was analyzed by non-linear regression (Hill equation)
to generate a dose response curve using SAS Software System (SAS institute, Inc., Cary,
NC). The calculated IC50 value is the concentration of the test compound that caused a
50% decrease in the maximal TNFa production. Preferred compounds from those found
in Table I and in the examples will exhibit an IC50 < 10 uM.
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Inhibition of other cytokines
By similar methods using peripheral blood monocytic cells, appropriate stimuli, and
commercially available ELISA kits (or other method of detection such as
5 radioimmunoassay), for a particular cytokine, inhibition of EL-1, G M -CSF, EL-6 and
EL-8 can be demonstrated (for example, see J.C. Lee et al., 1988, Int. J.
Immundpharmacol., 10, 835).
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What is claimed is
1 . A compound selected from the group consisting of:
l-(5-tert-Butyl-2-memoxy-phenyl)-3-[4-(2-isopropyl-6-memyl-pyrimidm-4-
yloxy)-naphthalen- 1 -yl]-urea;
l-(5-tert-Butyl-2-memoxy-phenyl)-3-[4-(2,6-dimemyl-pyrimidm-4-yloxy)-
naphthalen- 1 -yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(pyrmndin-4-yloxy)-naphthalen-l-yl]-
urea;
l-(5-tert-Butyl-2-memoxy-3-[l,2,4]triazol-4-yl-p^^
naphthalen- 1 -yl] -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-oxo-2H-pyran-4-yloxy)-naphthalen-l-
yl]-urea;
5 -tert-Butyl-2-methoxy-3 - { 3 - [4-(6-moipholin-4-ylmethyl-pyridin-3 -yl)-
naphthalen- 1 -yl]-ureido} -benzoic acid;
Carbonic acid 5-tert-butyl-2-memoxy-3-{3-[4-(6-morpholm-4-ylmethyl-pyridin-
3-yl)-naphthalen-l-yl]-ureido}-phenyl ester methyl ester;
l-(5-tert-Butyl-2-methoxy-phenyl)-3 -[4-(4-isopropylamino-[ 1 ,3 ,5]triazin-2-
yloxy)-naphthalen- 1 -yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(cyclopropylmethyl-amino)-
[ 1 ,3 > 5]triazin-2-yloxy]-naphthalen- 1 -yl} -urea;
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l-[4<4-Amino-[l 3 3,5]triazin-2-yloxy)-naplithalen-l-yl]-3-(5-tert-butyl-2-
methoxy-phenyl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-([l,3,5]triazin-2-yloxy)-naphthalen-l-yl]-
urea;
l-(5-tert-Butyl-2-mellioxy-phenyl)-3-[4-(2-cyclopropylamiiio-6-methyl-
pyrimidin-4-yloxy)-naphthalen- 1 -yl]-urea;
l-(5-tert-Butyl-2nme1hoxy-phenyl)-3-[4-(2-^
naphthalen- 1 -yl] -urea;
l-(5-tert-Bu1yl-2-methoxy-phenyl)-3-[4-(2-ethylamino-pyrimidm
naphthalen- 1 -yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-methy
yloxy)-naphthalen- 1 -yl]-urea;
l-[4-(2-Amino-6-methyl-pyrimi(hn-4-yloxy)-naph1halen-l-yl]-3-(5-tert-butyl-2-
methoxy-phenyl)-urea;
l-[4-(2-Ainino-pyrimidin-^
phenyl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-cyclopentylamino-pyrimidin^-yloxy)-
naphthalen- 1 -yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(cyclopropylmethyl-amino)-
pyrimidin-4-yloxy]-naphthalen- 1 -yl} -urea;
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l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(cyclopropylmethyl-amino)-6-methyl-
pyiimidin-4-yloxy]-naphthalen- 1 -yl} -urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3-(4- {2-[(tetrahydro-furan-2-ylmethyl)-
amino] -pyrimidin-4-yloxy } rnaphthalea- 1 -yl)-urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3-(4- {2-[(pyridin-2-ylmethyl)-amino]-
pyrimidin-4-yloxy } -naphthalen- 1 -yl)-urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(2-morpholin-4-yl-ethylamino>
pyrimidin-4-yloxy] -naphthalen- 1 -yl } -urea;
l-[4-(2-Benzylamino-pyrimidin-4-yloxy)-naphthalen-l-yl]-3-(5-tert-bu^^
methoxy-phenyl)-urea;
l-[4-(2-sec-Butylainino-pyriniidin^
methoxy-phenyl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(2-methoxy-ethylamino)-pyrimidm^
yloxy]-naphthalen- 1 -yl}-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(2-diraethylamino-ethylamhio)-
pyrimidin-4-yloxy]-naphthalen- 1 -yl} -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2^
naphthalen- 1 -yl]-urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-pyrrolidin- 1 -yl-pyrimidin-4-yloxy)-
napb.tb.alen- 1 -y 1] -urea; .
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l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-^
yloxy)-n.aphthalen-l-yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-^
naphthalen- 1 -yl]-urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3 - {4-[2-(4-methyl-piperazin- 1 -yl)-pyrimidin-
4-yloxy]-naphthalen-l-yl}-urea;
l-(5-tert-Bu1yl-2-methoxy-phenyl)-3-[4-(2-ethoxy-pyrimidin-4-yloxy)-
naphthalen- 1 -yl]-urea;
l-(5-tert-Butyl-2-methoxy-pheuyl)-3-{4-[2-(2-morpholin^-yl-ethoxy)-pyriiiiidiii-
4-yloxy]-naphthalen- 1 -yl} -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(2-dimethylamino-ethoxy)-pyrimi
4-yloxy]-naphthalen-l-yl}-urea;
1 -[4-(2-Ben2ylamino-pyrirjiidin-4-yloxy)-naphtlialen- 1 -yl]-3 -(5 -tert-butyl-2-
methoxy-3-[ 1 ,2,4]triazol-4-yl-phenyl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-^
naphthalen- 1 -yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-methylsulfanyl-pyrimidin^-yloxy)-
naphthalen- 1 -yl]-urea;
l-(2-Me1hoxy-5-trimethylsilanyl-phe^^
3-yl)-naphthalen-l-yl]-urea;
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H5-tert-Butyl-2-methoxy-phenyl)-3-{4-^^
yloxyj-naphthalen- 1 -yl} -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(3-methoxy-phenyl)-pyrimidin-4-
yloxyj-naphthalen- 1 -yl} -urea;
l-(5-tert-Butyl-2-met]ioxy-phenyl)-3-[4-(2-phenyl-pyriiiiidin-4-yloxy)-
naphthalen-1 -yl]-urea;
4-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-l-yloxy}-
pyrLmidine-2-carboxylic acid methyl ester;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-cy^
l-yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(tetrahydro-pyran-4-yloxy)-naphthalen--l-
yl]-urea
or the pharmaceutically acceptable derivatives thereof.
2. A compound selected from the group consisting of:
1 -[5-tert-Butyl-3-(l , 1 -dioxo- 1 -lambda-6-isotMazohdin-2-yl)-2-methoxy-phenyl]-
3-[4-(6-moipholm-4-ylmemyl-pyridin-3-yl)-naphthaIen-l-yl]-urea;
N-(3- {3-[4-(2-Armno-6-memyl-pyrunidin-4-yloxy)-naphthalen- 1 -yl]-ureido} -5-
tert-butyl-2-methoxy-phenyl)-methanesulfonamide;
N-(3-{3-[4-(2-Ammo-pyi±mdin-4-yloxy)-naphthalen-l-yl]-iireido}-5-tert-butyl-2-
methoxy-phenyl)-methanesulfonamide;
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N-(5-tert-Butyl-3-{3-[4-(2-cyano-pyri^
methoxy-phenyl)-metiaanesulfonamide;
N-(5-tert-Butyl-2-methoxy-3- {3 -[4-(tetrahydropyran-4-yloxy)-naphthalen- 1 -yl]-
ureido}-phenyl)-methanesulfonamide
N-(5-tert-Butyl-2-methoxy-3- {3 -[4-(pyrimidin-4-yIoxy)-naphthalen- 1 -yl]-
ureido}-phenyl)-methanesulfonamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-methylamino-pyrimidin-4-yloxy)-
naphtiialen- 1 -yl]-ureido } -phenyl)-methanesulfonamide;
N-(5-tert-Butyl-2-memoxy-3-{3-[4-(6-memyl-2-m^
yloxy)-naphthalen-l-yl]-ureido}-phenyl)-methanesulfonamide;
N-[5-tert-Butyl-3-(3-{4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yloxy]-
naphthalen- 1 -yl} -ureido)-2-methoxy-phenyl]-methanesulfonamide;
N-[5-tert-Butyl-3-(3-{4-[2-(cyclopropylmefhyl-amino)-6-methyl-pyrimidin-4-
yloxy]-naphthalen-l-yl}-ureido)-2-methoxy-phenyl]-methanesulfonamide;
N- {5-tert-Butyl-2-methoxy-3-[3-(4- {2-[(teti^ydro-fiiran-2-ylme1fayl)-aniiiio]-
pyrimidin-4-yloxy } -naphthalen- 1 -yl)-ureido]-phenyl} -methanesulfonamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-pyrroUdin-l-yl-pyrimidin-4^
naphthalen- 1 -yl]-ureido} -phenyl)-methanesulfonamide
or the phannaceutically acceptable derivatives thereof.
3. A compound selected from the group consisting of:
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l-[5-tert-butyl-2-(2-hydroxy-4-methyl-phenyl)-2H-pyrazol-3-yl]-3-[4-(2-
morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-urea;
145-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-{4-[2-(hydroxy)ethoxy]-naphthalen-
l-yl}-urea;
l-[5-tert-butyI-2-p-tolyl-2H-pyrazol-3-yl]-3-{4-[2-oxo-2-(morphoUn-4-yl)-
ethoxyj-naphthalen- 1 -yl} -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3- {4-[hydroxy]-naphthalen- 1 -yl} -urea
or the pharmaceutically acceptable derivatives thereof.
4. A compound selected from the group consisting of:
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(^^
naphthalen-1 -yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-^
naphthalen- 1 -yl]-urea;
H5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2^
yloxy]-naphthalen-l-yl}-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{2-[(pyridin-3-ylmethyl)-am^
pyrimidin-4-yloxy } -naphthalen- 1 -yl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-^
pyrimidin-4-yloxy } -naphthalen- 1 -yl)-urea;
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l-(5-tert-Butyl-2-meliioxy-phenyl)-3-(4-{2-[2<4-methyl-piperazm-l-yl)-
ethylamino]-pyrimidin-4-yloxy } -naphthalen- 1 -yl)-urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3 - {4-[2-(2-pyrrolidin- 1 -yl-ethylamino)-
pyrimidia-4-yloxy]-naphthalen-l -yl} -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(2-oxo-tetrahydro-furan-3-ylamm
pyrimidin-4-yloxy]-naphthalen-l -yl}-urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3 - {4-[2-(tetrahydro-furan-3 -ylamino)-
pyrimidin-4-yloxy]-naphthalen- 1 -yl} -urea;
l-(5-tert-Butyl-2-metfaoxy-phenyl)-3 -(4- {6-me1iiyl-2-[(tetrahydro-furan-2-
ylmethyl)-anuno]-pyrimidm^
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(2-methoxy-l-methyl-ethylamino)-
pyrimidin-4-yloxy] -naphthalen- 1 -yl} -urea;
2-(4- {4-[3 -(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen- 1 -yloxy } -
pyrirrudin-2-ylarj3ino)-propionamide;
2-(4-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-l-yloxy}-
pyrirrudin-2-ylamino)-N-melhyl-propionarnide;
2-(4- {4-[3 -(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen- 1 -yloxy} -
pyrirrudin-2-ylamino)-N ) N-dimethyl-propionarm
2-(4- {4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen- 1 -yloxy} -
pyrirnidin-2-ylamino)-N J N-dimethyl-acetamide
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l<5-tert-Butyl-2-methoxy-phenyI)-3-(4-{2-[l-(3-methoxy-phenyl)-etliylamino]-
pyrimidin-4-yloxy } -naphthalen- 1 -yl)-urea;
H4-{2-[l-(2-Bromo-phenyl)-ethylainino]-pyrin^
3-(5-tert-butyl-2-methoxy-phenyl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(4-diethylamino-l-methyl-
butylainino)-pyrimidin-4-yloxy]-naphthalen- 1 -yl} -urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-(4-methoxy-benzylanuno)-pyrimidin-
4-yloxy]-naphthalen- 1 -yl} -urea;
H5-tert-Buryl-2-methoxy-phenyl)-3-{4-[2-(3-c^
yloxy]-naphthalen-l-yl}-urea;
1 - {4-[2-(Beiizyl-methyl-amino)-pyrimidin-4-yloxy]-naphthalen- 1 -yl} -3-(5-tert-
butyl-2-methoxy-phenyl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{2-[(2-dimetbylarnino-ethyl)-methy^
amino]-pyrimidin-4-yloxy} -naphthalen- 1 -yl)-urea;
l-[4-(2-Benzylannno-6-methyl-pyrinndin-4-yloxy)-naphthalen-l-yl]-3-(5-tert-
butyl-2-methoxy-phenyl)-urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[6-methyl-2-(l -phenyl-ethylamino)-
pyrimidin-4-yloxy]-naphthalen- 1 -yl} -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-metty^^
aniino]-pyrimidin-4-yloxy } -naphthalen- 1 -yl)-urea;
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l-(5-tert-Butyl-2-methoxy-pheny^
methyl-pyrimidin-4-yloxy]-naphthalen- 1 -yl} -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-methyl-2-(2-morpholin-4-yl-
ethylamino)-pyrimidin-4-yloxy]-naphtiialen- 1 -yl} -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-dimethylamino-6-methyl-pyriim
yloxy)-naphthalen- 1 -yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-morpholm-4-yl-pyrimidin-4-yloxy)-
naphthalen-l-yl]-ureido}-phenyl)-methanesulfonamide;
N-[5-tert-Butyl-2-methoxy-3-(3-{4-[2-(l-phenyl-e%lamino)-pyrimidin-4-yloxy]-
naphthalen-l-yl}-ureido)-phenyl]-methanesulfonamide;
N-[5-tert-Butyl-2-metiioxy-3-(3-{4-[6-methyl-2-(l-phenyl-ethylamino)-
pyrimidin-4-yloxy]-naphthaIen- 1 -y 1} -weido)-phenyl]-methanesulfonamide;
N-{5-tert-Butyl-2-metlioxy-3-[3-(4-{2-[(pyrid^
yloxy}-naphthalen-l-yl)-iu:eido]-phenyl}-methanesulfonamide;
N-[5-tert-Butyl-3-(3-{4-[2-(2-dimethyIamino-ethyIariuno)-pyrimidin-4
naphthalen-l-yl}-ureido)-2-methoxy-phenyl]-methanesulfonamide;
N-[5-tert-Bu1yl-3-(3-{4-[2-(2-dimetty^
yloxy]-naphthalen- 1 -yl} -ureido)-2-methoxy-p]ienyl]-methanesulfonarnide;
N-[5-tert-Butyl-2-methoxy-3-(3-{4-[2-(2-morpholin-4-yl-ethylamino)-pyrimid^
4-yloxy]-naphthalen-l-yl}-nreido)-phenyl]-methanesulfonamide;
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N-[5-tert-Butyl-2-methoxy-3-(3-{4-[6-melhyl-2-(2-morpholin^-yl-ethylamino)^
pyrimidin-4-yloxy]-naphthalen- 1 -yl} -ureido)-phenyl]-methanesulfonamide;
N-(5-tert-Butyl-3-{3-[4-(2-dimethylainino-pyrimidin-4-yloxy)-na
ureido}-2-methoxy-phenyl)-methanesulfonamide;
N-[5-tert-Butyl-2-methoxy-3 -(3 - {4-[2-(4-methyl-piperazin- 1 -yl)-pyrimidin-4-
yloxy]-naphthalen-l-yl}-iireido)-phenyl]-methanesulfonarnide;
N-(54ert-Butyl-2-methoxy-3-{3-[4-(2-piperidin-l-yl-pyrimidin-4-yloxy)-
naphthalen-l-yl]-ureido}-phenyl)-methanesulfonamide;
N-{5-tert-Butyl-3-[3-(4-{2-[(2-dimemylaimno-emy^
yloxy} -naphthalen- l-yl)-ureido]-2-methoxy-phenyl} -methanesulfonamide;
N-[5-tert-Bu1yl-2-methoxy-3-(3-{4-[2-(tetrahydrofuran-3-ylamino)-pyrinu
yloxy]-naphthalen-l-yl}-iireido)-phenyl]-me1hanesulfonarnide;
N-[5-tert-Butyl-2-methoxy-3-(3- {4-[2-(2-methoxy- 1 -memyl-emylamino)-
pyrimidin-4-yloxy]-naphthalen- 1 -y 1} -ureido)-phenyl]-methanesiilfonaniide;
2-(4-{4-[3-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-ureido]-
naphthalen- 1 -yloxy} -pyrirtudin-2-ylairiino)-N-methyl-propionamide;
2-(4-{4-[3-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-ureido]-
naphthalen- 1 -yloxy} -pyrimidin-2-ylamino)-N,N-(limethyl-propionainide;
N- {5-tert-Butyl-2-methoxy-3-[3-(4- {2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-4-
yloxy } -naphthalen- 1 -yl)-ureido]-phenyl} -methanesulfonamide;
58
WO 02/092576 PCT/US02/14733
N- {5-tert-Butyl-2-methoxy-3-[3^4- {6-^^
amino]-pyrimidin-4-yloxy} -naphthalen- l-yl)-ureido]-phenyl} -
methanesulfonamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-methyl-2-pyrroUdin-l-yl-pyriiiu
yloxy)-naphthalen- 1 -yl]-xireido} -phenyl)-methanesulfonamide;
2-(5-tert-Butyl-2-methoxy-3-{3-[4-(pyridin^-yloxy)-naphthalen-l-yl]-ureido}-
phenylamino)-thiazole-4-carboxylic acid ethyl ester;
2-(5-tert-Butyl-2-methoxy-3- {3-[4-(2-pyrrolidin- 1 -ylmethyl-pyridin-4-yloxy)-
naph1halen-l-yl]-Tareido}-phenylaraino)-thiazole-4-carboxylic acid ethyl ester;
2-[5-tert-Bu1yl-2-methoxy-3-(3-{4-[2-(pyrroUdine-l-carbonyl)-pyridin-4-yloxy]-
naphthalen-l-yl}-vireido)-phenylamirio]-thiazole-4-carboxylic acid ethyl ester;
2-(5-tert-Buryl-2-me1hoxy-3-{3-[4-(2-methylaminomethyl-pyridin-4-yloxy)-
naphthalen-l-yl]-ureido}-phenylarnino)-thiazole-4-carboxylic acid ethyl ester;
2-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-methylcarbamoyl-pyridin-4-yloxy)-
naphthalen-l-yl]-iireido}-phenylaiiuno)-thiazole-4-carboxylic acid ethyl ester;
2-(5-tert-Butyl-2-methoxyO-{3-[4-(2-methylar^
1 -yl]-ureido} -phenylamino)-thiazole-4-carboxylic acid ethyl ester;
l-{5-tert-Butyl-2-methoxyO-[4-(pyn-olidine-l-carbonyl)-tbiazol-2-ylamino]-
phenyl} -3-[4-(pyridin-4-yloxy)-naphthalen- 1 -yl]-urea;
1 -[5-tert-Butyl-2-methoxy-3-(4-pyrrolidin-l -ylmethyl-thiazol-2-ylamino)-
phenyl]-3-[4-(pyridin-4-yloxy)-naphthalen-l-yl]-urea;
59
WO 02/092576 PCT/US02/14733
2-(5-tert-ButyI-2-methoxy-3- {3-[4-(pyrimidin-4-yloxy)-naphthalen-l -yl]-ureido} -
phenylamino)-thiazole-4-carboxylic acid ethyl ester;
2-(3- {3-[4-(2-Amino-pyrimidin-4-yloxy)-naphthalen- 1 -yl]-ureido } -5-tert-butyl-2-
methoxy-phenylamino)-thiazole-4-carboxylic acid ethyl ester;
2-(5 -tert-Butyl-2-methoxy-3- {3-[4-(2-methylamino-pyrimidin-4-yloxy)-
naphthalen-l-yl]-ureido}-phenylamino)-thiazole-4-carboxylic acid ethyl ester;
2-[5-tert-Butyl-3-(3-{4-[2-(cyclopropylmethyl-ai^
naph1halen-l-yl}-meido)-2-me1hoxy-phenylainino]-thiazole-4-carboxylic acid
ethyl ester;
2-(5-tert-Butyl-2-methoxy-3- {3-[4-(pyrimidin-4-yloxy)-naphthalen- l-yl]-ureido } -
phenylamino)-thiazole-4-carboxylic acid (2-dimethylamino-ethyl)-methyl-amide;
1 - {5-tert-Butyl-2-methoxy-3 -[4-(pyrrolidine- 1 -carbonyl)-thiazol-2-ylamino]-
phenyl}-3-[4-(pyrimidin-4-yloxy)-naphthalen-l-yl]-urea;
l-[5-tert-Butyl-2-methoxy-3-(4-pyrrohdin-l-^
phenyl]-3-[4-(pyrimidin-4-yloxy)-naphthalen- 1 -yl]-urea;
l-[5-tert-Butyl-2-me^oxy-3-(4-pyrrolidin-l-ylmethyl-1hiazol-2-ylamino)-
phenyl]-3-[4-(2-isopropylamino-pyrirnidiri-4-yloxy)-naphthalen- 1 -yl]-urea;
1 - {5-tert-Butyl-2-methoxy-3-[4-(pyrroUdine- 1 -carbonyl)-thiazol-2-ylamino]-
phenyl}-3-{4-[2-(cyclopropylme1hyl-amino)-6-methyl-pyrimidin-4-yloxy]-
naphthalen- 1 -yl } -urea;
l-[5-tert-Butyl-2-methoxy-3-(4-pyrrolidm^
phenyl]-3-{4-[2-(cyclopropylmethyl-amino)-6-methyl-pyrimidiQ-4-yloxy]-
naphthalen-l-yl}-urea;
60
WO 02/092576 PCT/US02/14733
l-[5-tert-Butyl-3-(3-dimethylamino-^^
[4-(pyridin-4-yloxy)-naphthalen- 1 -yl]-urea;
l-[5-tert-Butyl-3-(3-dimethylaminomethyl)-2-methoxy-phenyl]-3-[4-(pyridin-4-
yloxy)-naphtb.alen- 1 -yl]-urea;
l-[5-tert-Butyl-3-(3-dimethylamino-pyrroUdin-l-ylmethyl)-2-met3ioxy-ph^
[4-(2-dimeiiylaminomethyl-pyridin-4-yloxy)-iiaphtbalen-l-yl]-urea;
1 -[5-tert-Butyl-3-(3-dime1hylamino-pyrrolidin- 1 -ylmethyl)-2-methoxy-phenyl]-3-
[4-(pyrimidin-4-yloxy)-naphthalen- 1 -yl] -urea;
1 -[4-(2-Amino-pyriinidiii-4-yloxy)-naphtlialen- 1 -yl]-3-[5-tert-butyl-3-(3-
dimethylamino-pyrrolidin- 1 -ylmethyl)-2-methoxy-phenyl]-urea;
l-[4-(2-Arnino-6-methyl-pyrinu^i^^
(3-dimethylamino-pyrroUdin-l-ylmethyl)-2-methoxy-phenyl]-iirea
l-(5-tert-Butyl-3-dime11iylaminomem^
(cyclopropylmethyl-amino)-pyrinudin-4-yloxy]-naphthalen-l-yl}
1 -(5-tert-Butyl-3-dimethylaminomethyl-2-methoxy-phenyl)-3- {4-[2-
(cyclopropylme1iiyl-aiimo)-6-methyl-pyrimidm-4-yloxy]-M
N-[5-tert-Butyl-2-methoxy-3-(3-{4-[2-(2-me1hoxy-phenyl)-pyrimidin-4-yloxy]-
naphthalen- 1 -yl} -ureido)-phenyl]-methanesulfonamide;
4-{4-[3-(5-tert-Butyl-3-methanesulfonylaiiiino-2-methoxy-plienyl)-ureido]-
naphthalen-l-yloxy}-pyrimidine-2-carboxylic acid methyl ester;
61
WO 02/092576
PCT/US02/14733
1 -[4-(2-Acetyl-pyrimidin-4-yloxy)-naphthalen- 1 -yl]-3-(5-tert-butyl-2-methoxy-
phenyl)-urea;
N-(3-{3-[4-(2-Ace1yl-pyrirmdin-4-ylox^^
methoxy-phenyl)-methanesulfonamide;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[2-( 1 -pyrrolidin- l-yl-ethyl)-pyriroidin-4-
yloxy]-naphthalen-l -yl}-urea;
N-[5-tert-Butyl-2-memoxy-3-(3-{4-[2-(l-pyiroU^
yloxy]-naphthalen- 1 -yl} -ureido)-phenyl]-methanesulfonamide;
l-(2-methoxy-5-trimethylsilanyl-phenyl)-3-{4-[2- (cyclopropylmethyl-amino)-
pyrimidin-4-yloxy]-naphthalen- 1 -yl} -urea
or the pharmaceutically acceptable derivatives thereof.
5 5. A pharmaceutical composition comprising a pharmaceutically effective amount of a
compound according to claims 1, 2, 3 or 4.
6. A method of treating a cytokine mediated disease or condition which comprises
administering to a patient in need of such treatment a therapeutically effective amount of
10 a compound according to claims 1, 2, 3 or 4.
7. The method according to claim 6 wherein cytokine mediated disease or condition is
selected from rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis,
multiple sclerosis, Guillain-Barre syndrome, psoriasis, graft versus host disease, systemic
15 lupus erythematosus, percutaneous transluminal coronary angioplasty, diabetes, toxic
shock syndrome, Alzheimer's disease, acute and chronic pain, contact dermatitis,
62
WO 02/092576
PCT/US02/14733
atherosclerosis, traumatic arthritis, glomerulonephritis, reperfusion injury, sepsis, bone
resorption diseases, chronic obstructive pulmonary disease, congestive heart failure,
asthma, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome
(ARDS), multiple organ injury secondary to trauma, dermatoses with acute inflammatory
5 components, acute purulent meningitis, necrotizing entrerocolitis, syndromes associated
with hemodialysis, leukopherisis and granulocyte transfusion.
8. The method according to claim 7 wherein the disease is selected from rheumatoid
arthritis, osteoarthritis, Crohn's disease, psoriasis, ulcerative colitis, osteoporosis, chronic
10 obstructive pulmonary disease, percutaneous transluminal coronary angioplasty and
congestive heart failure.
9. The method according to claim 8 wherein the disease is selected from rheumatoid
arthritis, Crohn's disease, psoriasis, chronic obstructive pulmonary disease, percutaneous
15 transluminal coronary angioplasty and congestive heart failure.
63
INTERNATIONAL SEARCH REPORT
Intema^nal Application No
PCT/US 02/14733
A. CLASSIFICATION OF SUBJECT MATTER
IPC 7 C07D239/34 A61K31/505 C07D251/42 C07D239/47 C07D417/12
C07D401/12 C07D231/40 A61P29/00
According lo International Patent Classification (IPC) or to both national clasdflcallon and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
IPC 7 C07D A61K A61P
Documentation searched other than minimum documentation to the extent thai such documents are included in the fields searched
Electronic data base consulted during the International search (name of data base and, where practical, search terms used)
EPO-Internal , WPI Data, CHEM ABS Data
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category " Citation of document, with Indication, where appropriate, of the relevant passages
Relevant lo claim No.
X
X
WO 00 55139 A (80EHRIMGER INGELHEIM
PHARMA) 21 September 2000 (2000-09-21)
page 68-85 -page 107-121; claim 17
page 17-18
W0 00 43384 A (BOEHRIMGER INGELHEIM
PHARMA) 27 July 2000 (2000-07-27)
example 4
W0 01 36403 A (B0EHRINGER INGELHEIM PHARMA
;BREITFELDER STEFFEN (US); HAO MING HO)
25 May 2001 (2001-05-25)
the whole document
1,2,4,5
3
3
1,2,4,5
□
Further documents are listed in the continuation of box C.
LO
Patent family members are listed In annex.
• Special categories of died documents :
'A' document defining the general state of the art which Is not
considered to be of particular relevance
*E' earlier document but published on or after the International
filing date
•L" document which may throw doubts on priority clalm(s) or
which Is cited lo establish the publication data of another
citation or other special reason (as- specified)
'O* document referring lo an oral disclosure, use, exhibition or
other means
•P* document published prior to the International fling date but
later than the priority date claimed
*T* later document published after the International filing date
or priority date and not In conflict with the application but
died to understand the principle or theory underlying the
invention
'X' document of particular relevance; the claimed Invention
cannot be considered novel or cannot be considered to
involve an Inventive step when the document Is taken alone
*Y* document of particular relevance; the claimed Invention
cannot be considered to Involve an Inventive step when the
document is combined with one or more other such docu-
ments, such combination being obvious to a person skilled
In the art.
'&' document member of the same patent family
Date of the actual completion of the International search
3 July 2002
Date of mailing of the international search report
11/07/2002
Name and mailing address of the ISA
European Patent Office, P.B. 581 B Patentlaan 2
NL-2280 HVRIJswI|k
TeL (+31-70) 340-2040, Tx. 31 651 epo nL
Fax: (+31-70) 340-3016
Authorized officer
Lauro, P
Rum PCTflSA/aiO (second cheat) (July 1092)
INTERNATIONAL SEARCH REPORT
Intentional application No.
PCT/US 02/14733
Box I Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet)
This International Search Report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:
1- H Claims Nos.:
because they relate to subject matter not required to be searched by this Authority, namely:
Although claims 6-9 are directed to a method of treatment of the human/animal
body, the search has been carried out and based on the alleged effects of the
compound/composition.
2. | | Claims Nos.:
because they relate to parts of the International Application that do not comply with the prescribed requirements to such
an extent that no meaningful International Search can be carried out, specifically:
3. | | Claims Nos.:
because they are dependent claims and are not drafted In accordance with the second and third sentences of Rule 6.4(a).
Box II Observations where unity of invention is lacking (Continuation of Item 2 of first sheet)
This International Searching Authority found multiple Inventions In this International application, as follows:
1. I | As all required additional search fees were timely paid by the applicant, this International Search Report covers all
' — ' searchable claims.
2. As all searchable claims could be searched without effort justifying an additional fee, this Authority did not Invite payment
of any additional fee.
3. I I As only some of the required additional search fees were timely paid by the applicant this International Search Report
' — ' covers only those claims for which fees were paid, specifically claims Nos.:
4. | | No required additional search fees were timely paid by the applicant Consequently, this International Search Report is
restricted to the invention first mentioned in the claims; it is covered by claims Nos.:
Remark on Protest | ] The additional search fees were accompanied by the applicant's protest
| " | No protest accompanied the payment of additional search fees.
Form PCrr/iRA/pm fmntlnuation of first sheet (11) fJulv 199tn
INTERNATIONAL SEARCH REPORT
omuii writ paitnn
Intern^^Bdl Application No
PCT/US 02/14733
Patent document
cited in search report
Publication
Patent family
msmbsr(s)
Publication
date
WO 0055139
21-09-2000
W0 0043384
27-07-2000
WO 0136403
25-05-2001
AU
2881700
A
04-!0-2000
Db
lObooU
A
31-05-2002
DD
BR
0008922
A
15-01-2002
ft m
CN
1349509
T
15-05-2002
CZ
mm loon
20013289
A3
16-01-2002
EP
1165516
A2
ft ft ft *i ftft ft n
02-01-2002
NO
20014412
A
H 1 ft ft ft ft ft i
11-09-2001
TR
200102817
T2
21-05-2002
WO
0055139
A2
ft t ft ft ft ft ft ft
21-09-2000
us
6358945
Bl
19-03-2002
us
2002055507
Al
09-05-2002
A 1 1
AU
1752200
A
07-08-2000
n ft
BG
105653
A
31-01-2002
BR
9916930
A
ft ft "t « ft ft "4
30-10-2001
CN
1333767
T
30-01-2002
CZ
20012635
A3
14-11-2001
LP
1147104
Al
ft A ft ft ft ft 4
24-10-2001
IMU
20013559
A
*I O ft ~~J oft ft 1
18-07-2001
SK
10192001
A3
03-12-2001
WO
0043384
Al
27-07-2000
US
6319921
Bl
20-11-2001
US
6333325
Bl
25-12-2001
US
2002058678
Al
16-05-2002
US
6329415
Bl
11-12-2001
US
2002065285
Al
30-05-2002
US
6372773
Bl
16-04-2002
AU
1617901
A
30-05-2001
W0
0136403 Al
25-05-2001
Forni PCT/1SA/210 (patent family amax)(July 1892)